Search

Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.

AML patients under the age of 60 whose blasts harbor a FLT3 internal tandem duplication (ITD) mutation have a higher relapse rate and inferior survival compared to those without this mutation. To determine if FLT3ITD also carries a negative prognostic impact in older adults receiving therapies commonly used in this age group, we retrospectively analyzed outcomes of patients ≥60 years with CN-AML according to FLT3 mutation status. We identified 91 newly diagnosed CN-AML patients, 55 with wild-type FLT3 and 36 with FLT3ITD. Of the 91 patients, 36 received supportive care and/or experimental therapies while the remaining 55 received induction chemotherapy, followed by allogeneic SCT in 17 of these patients. Based on univariate analysis, advanced age at diagnosis was significantly associated with shorter overall survival (OS) (p < .0001) while intensive therapies were associated with improved OS (p < .0001). In a multivariate analysis that accounted for type of treatment, patient age, gender, and WBC count, FLT3ITD was significantly associated with shorter OS compared to wtFLT3 [p = .001; hazard ratio (HR) = 2.23; 95% CI: 1.35–3.70]. Our data support the negative prognostic impact of FLT3ITD in older adults with CN-AML.

Purpose: Chronic lymphocytic leukemia (CLL) cells treated with dasatinib in vitro undergo apoptosis via inhibition of Lyn kinase. Thus, in this study we tested the activity of dasatinib in patients with relapsed CLL. Experimental Design: Patients were eligible for this phase II trial if they had documented CLL/SLL and had failed at least 1 prior therapy with a fludarabine-containing regimen and if they required therapy according to NCI-WG criteria. The starting dose of dasatinib was 140 mg daily. Results: Fifteen patients were enrolled, with a median age of 59 and a median of 3 prior regimens. All patients had received fludarabine, and 5 were fludarabine-refractory. Eleven of the 15 (73%) had high risk del(11q) or del(17p) cytogenetics. The primary toxicity was myelosuppression, with grade 3 or 4 neutropenia and thrombocytopenia in 10 and 6 patients, respectively. Partial responses by NCI-WG criteria were achieved in 3 of the 15 patients (20%; 90% CI: 6–44). Among the remaining 12 patients, 5 had nodal responses by physical exam, and 1 patient had a nodal and lymphocyte response but with severe myelosuppression. Pharmacodynamic studies indicated apoptosis in peripheral blood CLL cells within 3 to 6 hours after dasatinib administration, associated with downregulation of Syk (spleen tyrosine kinase) mRNA. Conclusions: Dasatinib as a single agent has activity in relapsed and refractory CLL. Clin Cancer Res; 17(9); 2977–86. ©2011 AACR.

Background: Aurora kinases play essential roles in regulating cell division, and increased expression has been noted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We previously conducted a phase I study of alisertib combined with "7+3" induction chemotherapy in untreated patients with AML, and found the combination to have an adverse event profile similar to 7+3 alone, with promising efficacy, particularly for patients with high-risk disease, such as those who were older, with high-risk molecular features, or with secondary AML. These patients collectively have a historically grim prognosis, with an approximate rate of remission, in trials, of 45%. CPX-351, a liposomal daunorubicin-cytarabine product, was recently approved for use in secondary AML after it was demonstrated to be superior to 7+3 induction, with a median survival of 9.6 months versus 5.9 months among older patients, in a phase 3 trial. We recently completed accrual to a phase II study of alisertib plus induction chemotherapy in patients with untreated, high-risk AML. Methods: Patients were eligible if they had AML defined by WHO 2016 and either an adverse-risk karyotype (European Leukemia Net Guidelines), secondary (post-MDS/MPN) AML, therapy-related AML, or age ≥ 65 vears. We used a Simon two-stage design, assuming a null composite remission rate (complete remission [CR] and CR with incomplete count recovery [CRi]) of 45%. Patients could be enrolled prior to cytogenetic classification, but those without adverse-risk karyotype who lacked other eligibility criteria were removed before day 8 and replaced. All patients received continuous infusion cytarabine 100mg/m2 on days 1-7 [D1-7] and idarubicin 12mg/m2 [or daunorubicin 60mg/m2] D1-3 (7+3). On D8 through D15, alisertib at 30mg BID orally (PO) was administered. All underwent a mid-induction marrow biopsy to assess for residual disease, which if present, was treated with 5+2 re-induction without alisertib. Following remission, patients could receive up to 4 consolidation cycles with cytarabine (3g/m2 BID D1,3,5 for age Results: 39 eligible patients were enrolled. The median age was 67 (range 33-83); 25 (64%) were male, and 33 (85%) were Caucasian. 22 patients (56%) had secondary AML (16 with antecedent MDS, 2 with antecedent CMML, 1 with antecedent MPN, and 3 with therapy-related AML). 13 (33%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (18%), NPM1 in 7 (18%), IDH1 in 5 (13%), IDH2 in 5 (13%), CEBPA in 3 (8%), and TP53 mutations in 4 (10%) patients. 33 patients (85%) demonstrated an ablated marrow at mid-treatment, and six (15%) received re-induction at mid-treatment. 8 patients (21%) were refractory to induction, and five (13%) died prior to response assessment due to infection or bleeding. The 30-day and 60-day mortality rates were 8% and 13%, respectively. Patients experienced expected grade 4 toxicities of leukopenia, anemia, thrombocytopenia, and febrile neutropenia; no new attributable safety signals were detected. The CR+CRi rate was 64% (2-stage 95% CI 48-79%) with 20 patients (51%) achieving CR and 5 (13%) achieving Cri. The CR+CRi rate was 59% (13 of 22) in those with secondary AML, 67% (18 of 27) in those aged ≥ 65, 77% (10 of 13) in those with adverse risk karyotype, and 75% (3 of 4 patients) in patients with TP53 mutations. One (3%) patient achieved a partial remission. Based on the composite remission rate of 64%, the combination was deemed effective per study design. 5 patients have relapsed to date. 10 have received at least 1 cycle of consolidation, 16 patients (41%) have gone on to SCT. With a median follow-up of 14 months (Figure), the 12-month overall survival (OS) is 51% (37-65%). Although the data continues to mature, median OS is 12.2 months (90% CI 8.8-NA). In the subset of patients achieving a CR+CRi, the 12-month relapse-free survival was 52% (90% CI 34-67%). Conclusions: Alisertib, a novel aurora A kinase inhibitor, combined with conventional induction, is efficacious and demonstrates a promising rate of remission and survival among patients with previously untreated high-risk AML. Larger randomized studies are under consideration to better assess the promise of this novel combination. Figure. Figure. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. DeAngelo:Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; Amgen: Consultancy; Takeda: Honoraria; Blueprint Medicines: Honoraria, Research Funding. Amrein:Takeda: Research Funding. Steensma:Acceleron: Consultancy; Amphivena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; H3 Biosciences: Research Funding; Janssen: Consultancy, Research Funding; Kura: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Otsuka: Membership on an entity's Board of Directors or advisory committees; Syros: Research Funding; Takeda: Consultancy. Garcia:Celgene: Consultancy. Rosenblatt:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria.

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients >60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates of approximately 60% and 3-year survivals of less than 15% (Larson R., Hematology 2005). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as an early appreciation of the therapeutic promise, of adding ixazomib to standard multi-agent standard treatment for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Excluded were patients with mature ALL (including Burkitt's). Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible and tyrosine kinase inhibitor therapy was added to the chemotherapy on Day 10 for these patients. The induction treatment consisted of the following: Prednisone 40 mg/m2/day, Days 2-22 for patients Prednisone 40mg/m2/day Days 2-8 for patients ≥ 60 years of age; Vincristine (V) 2 mg IV on Days 2, 9, 16, 23; Doxorubicin (D) 30mg/m2/day on Days 2 and 3; intrathecal cytarabine 50 mg on Day 2; Intrathecal methotrexate 12 mg Day 29; G-CSF 300 mcg/kg sc or IV was started on Day 5 and continued until ANC was >2000 for 2 consecutive days. On Days 1, 8, 15, ixazomib was given orally at the dose prescribed according to 3 dose-escalation cohorts: 2.3 mg/day, 3.0mg/day, or 4.0 mg/day. A standard 3 +3 patient cohort dose escalation design was used to determine the dose of ixazomib for each patient. The primary objective of the study was to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients. After induction patients received consolidation I consisting of the following: cyclophosphamide 750 mg/m2/day, Days 2-3; prednisone 40 mg/m2/day, Days 2-6; PEG-asparaginase 500 units/m2 IV on Day 2 (for Ph- patients only); intrathecal methotrexate 12 mg on Days 2 and 15. On Days 1, 8, 15 of consolidation I, ixazomib was given orally at the dose previously prescribed for them during induction. After consolidation I, patients in complete remission (CR) with a suitable donor were offered stem cell transplantation as per institutional guidelines. Those not going to transplantation proceeded to continuation therapy as follows: CNS Phase: Intrathecal methotrexate 12 mg, cytarabine 40 mg, hydrocortisone 50 mg on days 1, 8, 15, vincristine Day 1, doxorubicin on Day 1, 6-MP Days 1-14, dexamethasone (DEX) Days 1-5, PEG-ASP Day 1+15 Consolidation II: 8 cycles of V + D + 6-MP + DEX + PEG-ASP; Maintenance Phase: V + DEX + 6+MP + oral methotrexate (ends after 18 months of remission). Results: The dose escalation phase completed with 9 patients. Among these patients, 4 harbored BCR-ABL1 rearrangements, all had B-ALL, the median age was 65 years, 78% were male, and 78% were performance status 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's, a grade 3 peripheral neuropathy and a grade 5 acute kidney injury. Grade 3 and 4 toxicities included grade 4 neutropenia in 8 patients and grade 4 thrombocytopenia in 7 patients. Two patients experienced grade 3 thrombocytopenia. There was 1 patient with a grade 2 neuropathy that did not meet the definition of DLT. Among the 9 patients, 7 (78%) achieved CR, and 2 patients went on to stem cell transplantation. Conclusions: A dose of 2.3 mg of ixazomib was well-tolerated in combination with induction chemotherapy among older patients with ALL, and is being tested in the expansion phase of this trial. The remission rate in this older adult population appears favorable in both Ph-negative and Ph-positive patients. Table. Table. Disclosures Amrein: Takeda: Research Funding. Fathi:Agios: Honoraria, Research Funding; Astellas: Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Introduction: AML and MDS are advanced myeloid malignancies more common among older adults and generally associated with poor outcomes. Allogeneic hematopoietic cell transplantation (HCT) may cure a proportion of affected patients, but disease relapse remains common and is associated with dismal survival. High doses of lenalidomide may modulate graft-vs-leukemia (GvL) effects, and have shown encouraging responses for relapsed AML. Bortezomib may also augment GvL and potentiate the effect of other chemotherapeutics. We conducted a phase I study of escalating doses of bortezomib added to high-dose lenalidomide in patients with AML and MDS, who had relapsed following HCT. Methods: We enrolled patients aged ≥ 18 years, with AML or MDS, relapsing after HCT in a '3+3' dose-escalation study. Patients with grade ≥3 GVHD, or chronic GVHD requiring >20mg/d of prednisone were excluded. Patients otherwise had to be off immunosuppressive therapy for 2 weeks. Lenalidomide 50mg/d was administered on days 1-21 of 28-day induction cycles. On days 2, 5, 9, and 12, subcutaneous bortezomib was administered at escalating dose levels: 0.7mg/m2, 1.0mg/m2, and 1.3mg/m2. Patients could receive up to two cycles of induction. After reaching the maximally tolerated dose (MTD), 9 patients were enrolled at the recommended phase II dose (RP2D) of bortezomib 1.3mg/m2. Dose limiting toxicities (DLTs) included G4 peripheral neuropathy, G3+ aGVHD, moderate/severe cGVHD, non-resolving G3/4 non-hematologic toxicities, and the inability to receive at least 50% of both drugs during induction. The DLT period spanned up to 2 induction cycles, but could be 1 cycle if a patient entered complete remission (CR) or complete remission with incomplete count recovery (CRi) after the first cycle. Response to induction was the best response after up to two cycles of induction and was assessed in those patients treated at the MTD/RP2D. Donor lymphocyte infusions (DLI) were allowed after induction per the treating physician. Results: A total of 21 patients were enrolled, with a median age of 66 years at study entry (range 23-74). The patients were predominately male (62%) and white (86%), while 2 patients (10%) identified as of Hispanic ethnicity. The majority had AML (19/21), with 10 of the AML patients having disease arising from prior CMML (1), MDS (7), or MPN (2). Three patients had del(5q); 2 patients had loss of 17p and 2 patients had complex cytogenetics. Three patients were enrolled at bortezomib dose levels of 0.7mg/m2 and 1.0mg/m2; at dose level 3, one patient experienced a DLT for receiving < 50% of doses and the cohort was expanded to 6 total patients. An additional 9 expansion patients were then treated at this dose level for a total of 15 patients treated with lenalidomide 50mg and bortezomib 1.3mg/m2. During dose expansion, grade 4 toxicities attributed to study drug included grade 4 neutropenia (n=5), thrombocytopenia (n=3), and febrile neutropenia (n=1), consistent with what was seen during dose escalation. Across all cohorts (n=21), 4 patients achieved CR/CRi. Of the 15 patients treated at the MTD/RP2D, 4 patients had progressive disease after the first induction cycle, and 2 patients stopped therapy during induction cycle 2. A total of 9 patients completed both induction cycles. Of the 15 patients treated at the RP2D, 3 achieved a CR/CRi (20%, 90%CI 5.7-44.0%). Another 2 patients had stable disease. One additional patient achieved a CR in the first dose cohort (Figure 1). Chimerism during treatment tracked with disease response; one patient with persistent low chimerism achieved CRi and received DLI as well (patient 3, who also harbored a TP53 mutation). A total of 3/13 patients tested harbored TP53 mutations; 2/3 achieved CRi while the third (patient 2) came off treatment during induction. Conclusions: Lenalidomide may be safely combined with bortezomib in patients with AML and MDS relapsing after HCT, with an encouraging rate of complete remission (20%) in this poor risk population. Overall toxicities with this regimen were manageable, and largely related to cytopenias. Of note, 2 of the 4 CR/CRi responses on the trial were in patients with TP53-mutated disease, suggesting that this regimen should be further evaluated in this high-risk population, and combination with donor lymphocyte infusion may also merit investigation in larger studies. Figure 1. Figure 1. Disclosures Brunner: Takeda: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding. Rosenblatt:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Amrein:Takeda: Research Funding. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding.

Background: Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) consisting of an antibody specific for human CD30, an anti-microtubule agent monomethyl auristatin E (MMAE), and a protease-cleavable linker attaching MMAE to the antibody. BV is efficacious therapy against certain CD30-expressing malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma, and is currently approved for use in these diseases. We and others previously demonstrated CD30 expression on a sizeable proportion of primary AML samples as well as cell lines. Given this data, we conducted a phase I dose-escalation trial of BV in combination with re-induction chemotherapy (MEC) for patients with relapsed or refractory AML. Methods: In this phase I, 3+3 cohort dose-escalation study, BV was administered 3 days prior to initiation of MEC re-induction for relapsed or refractory AML. Eligibility for enrollment included adults over age 18, adequate organ function, an ECOG performance status of ≤ 2, and a diagnosis of relapsed or refractory AML with > 20% CD30 expression (as assessed by immunohistochemistry or flow cytometric analysis). On day 1 of the trial, all enrolled participants were initiated on therapy with BV intravenously using three sequential dosing levels (0.9 mg/kg, 1.2 mg/kg, 1.8mg/kg). On day 3, patients were initiated on MEC re-induction chemotherapy (Mitoxantrone 10mg/m2 IV administration for five days [D3-8], etoposide 100mg/m2 IV D3-8, cytarabine 1000mg/m2 IV D3-8). The period of dose limiting toxicity (DLT) assessment occurred during the period of re-induction (approximately D1-35). Once dose escalation for BV reached a dose of 1.8 mg/kg IV, no further escalation would occur. An additional cohort of ten patients were to be treated at this maximum dose, or if a maximum tolerated dose (MTD) was reached, an additional 10 patients were to be treated at this dose. Thereafter, maintenance therapy with BV could be initiated, and administered IV every 21 days, as per dose level during prior re-induction, and continued for up to 12 months. Those eligible for stem cell transplant (SCT) were removed from study for this purpose. Results: 22 eligible patients were enrolled on study. The median age was 58 (range 23-72); 15 (68%) were male, and 20 (91%) were Caucasian. 7 patients (32%) had secondary AML (6 with antecedent MDS and 1 with therapy related AML). 6 (27%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (32%), NPM1 in 4 (18%), and CEBPA in 2 (9%). The median degree of blast CD30 expression in those assessed by flow cytometry was 92% (range 30-98%). 6 patients had refractory disease, while the remaining had relapsed AML at time of enrollment. 10 patients (46%) had undergone prior allogeneic stem cell transplantation (SCT), one of whom had undergone two prior stem cell transplants. Three patients were treated at dose level 1, 5 at dose level 2, and 4 at dose level 3. Two of the patients treated at dose level 2 were removed prior to end of DLT period due to lack of response and were replaced, and 1 patient treated at dose level 3 died due to infectious complications prior to end of DLT monitoring period and was replaced. No new attributable toxicities apart from that expected from MEC re-induction alone were seen with the combination therapy. No DLTs were detected, and the recommended phase 2 dose (RP2D) was deemed to be dose level 3 (1.8 mg/kg). An additional 10 patients were treated at the RP2D. Overall, 4 patients achieved a complete remission (CR) and 4 achieved a complete remission with incomplete hematologic recovery (CRi), for a composite remission rate (CCR) of 36% (8/22). Among the 14 patients treated at the RP2D of 1.8mg/kg, 6 achieved a CR or CRi (CCR 43%). Of the remaining cases, one was replaced prior to response assessment and the others experienced progressive disease. The degree of baseline CD30 expression by flow cytometry did not appear to predict for response in this phase 1 dose escalation study, although study of correlative samples is ongoing. Conclusions: BV is well tolerated when administered in conjunction with conventional re-induction chemotherapy in patients with relapsed-refractory AML, in whom CD30 is an intriguing target. Adverse events on this study were predominantly expected and related to marrow suppression from MEC re-induction. No DLT was identified. Additional and larger studies are needed to more comprehensively assess the efficacy of CD30-targeted therapy in AML. Disclosures Fathi: Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Emadi:NewLink Genetics: Research Funding. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Amrein:Takeda: Research Funding.

Background: Older patients with AML face difficult treatment decisions as they can be treated either with multi-drug 'intensive' chemotherapy requiring a prolonged hospitalization, or 'non-intensive' chemotherapy. Although intensive chemotherapy is often perceived by clinicians as more burdensome, studies comparing patients' quality of life (QOL) and psychological distress while receiving these treatments are lacking. Methods: We conducted a longitudinal study of older patients (≥ 60 years) newly diagnosed with AML receiving intensive (i.e. 7+3: cytarabine/anthracycline combination) or non-intensive (i.e. hypomethylating agents) chemotherapy at two tertiary care hospitals. We assessed patient's QOL [Functional Assessment of Cancer Therapy-Leukemia], and psychological distress [Hospital Anxiety and Depression Scale [HADS]] at baseline and 2, 4, 8, 12, and 24 weeks after diagnosis. We compared the proportion of patients in each group reporting clinically significant depression or anxiety (HADS subscale cut off ≥ 7) and used mixed linear effects models to compare QOL and psychological distress longitudinally between groups. Results: We enrolled consecutive patients within 72 hours of initiating intensive (n=50) or non-intensive (n=50) chemotherapy. There were no differences in baseline QOL, depression, or anxiety symptoms between the groups. At baseline, 33.33% (33/100) and 30% (30/100) of the overall cohort reported clinically significant depression and anxiety, respectively, with no differences between groups. At 4 weeks, 41.98% (34/81) of patients in the overall cohort reported clinically significant depression, with no differences between groups. In mixed linear effects models, there were no differences in QOL (β=-0.71, SE=1.12, P=0.527), depression (β=0.24, SE=0.20, P=0.226), or anxiety (β=-0.16, SE=0.19, P=0.386) symptoms between groups over time. Conclusion: Older patients with AML receiving intensive and non-intensive chemotherapy experience similar QOL impairments and high rates of psychological distress. These findings underscore the need to develop supportive care interventions for older patients with AML, regardless of their initial treatment strategy. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. DeAngelo:ARIAD: Consultancy, Research Funding; Takeda: Honoraria; Amgen: Consultancy; Shire: Honoraria; Blueprint Medicines: Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; BMS: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria. Amrein:Takeda: Research Funding.

Background Recurrent mutations in the spliceosome complex are seen in myeloid malignancies, including acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelodysplastic syndromes (MDS). Mutations are detected most frequently in SF3B1, SRSF2, or U2AF1, and are largely mutually exclusive. Recently, a novel SF3B1 modulator, H3B-8800, entered phase-I clinical trials. While the impact of spliceosome mutations at diagnosis and at the time of transplant has been described, there is limited data about the outcomes of patients with splicing factor-mutated disease after the initiation of standard frontline chemotherapies: induction chemotherapy (IC) or hypomethylating agents (HMA). Methods Patients with MDS, CMML, or AML with a spliceosome mutation and treated with chemotherapy were identified. Disease risk was assessed using standard criteria (IPSS-R for MDS, ELN for AML, and CPSS for CMML). Overall survival (OS) was defined as the time from start of treatment until death and censored at last known alive. Event free survival (EFS) was defined as the time from start of treatment until relapse, new therapy, or death. We identified the first therapy for newly diagnosed disease (induction chemotherapy, HMA, bone marrow transplant, or other), and grouped remissions as CR (complete remission) or CRi (complete remission with incomplete hematologic recovery). Outcomes were assessed by disease type, mutation, and initial therapy. EFS and OS were estimated by the method of Kaplan and Meier. Results We identified 88 patients diagnosed with AML, CMML, or MDS harboring a mutation in SF3B1 (n=24), SRSF2 (n=43), or U2AF1 (n=21). The median follow-up of the cohort was 637 days. The median age at diagnosis was 69.5 years (33-90), and there was no difference according to mutation (p=0.907). A diagnosis of AML was slightly more common among patients with SRSF2 mutations at the time of treatment, but this was not statistically significant (27/43, p=0.07). Patients with SF3B1 mutations were less likely to have co-mutated ASXL1 (12%, vs 42% with U2AF1 and 40% with SRSF2, p=0.0384). SRSF2 disease more often had co-mutated IDH2 (26%, vs 0% with U2AF1 and 4% with SF3B1, p=0.01). Other co-mutations did not vary significantly between U2AF1, SF3B1, or SRSF2-mutated disease (Figure 1). Patients who had a mutation in SF3B1 had a longer duration from diagnosis to first therapy (median 65 days, range 0-1159) than those with U2AF1 (median 39d) or SRSF2 (median 9d) mutations (p=0.045). A total of 31 patients received induction chemotherapy, while 50 received HMA as initial therapy; 3 patients were transplanted, and 5 received other chemotherapies (e.g. enasidenib). The remission rate for patients treated with induction was 55%, and there was no difference in rate of remission (CR+CRi) according to mutation type (U2AF1 50%, SF3B1 60%, SRSF2 53%, p=1.00). Patients treated with HMA had a remission rate of 22%, with a trend toward lower remission rates in SF3B1-mutated disease (0/11, vs. U2AF1 20% and SRSF2 33%, p=0.08). We performed a multivariate analysis for overall survival incorporating mutation type, initial treatment, disease risk group, age at the time of treatment, and disease (MDS, AML, or CMML). Compared to MDS, there was no difference in OS according to whether patients had splicing-factor mutated AML (p=0.45) or CMML (p=0.61) (Figure 2). Interestingly, although CR rates differed between all patients receiving induction or HMA, there was no difference in OS between these same groups (Figure 3, p=0.803). Conclusion In this study, there was no difference in response to frontline treatment for SF3B1-mutated myeloid malignancies compared to U2AF1- or SRSF2-mutated disease. Interestingly, there was no difference in survival according to whether patients had splicing-factor mutated AML, MDS, or CMML at the time of treatment; moreover, there was no difference in survival with induction compared to HMA therapy. Together, these point to a rationale to include AML, MDS, and CMML patients together on trials targeting these mutations, and the general need to improve on the poor outcomes with standard induction or HMA therapy. Disclosures Amrein: Takeda: Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Jazz: Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Brunner:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding.

154 Background: Older patients with AML face difficult treatment decisions as they can be treated either with multi-drug ‘intensive’ chemotherapy requiring a prolonged hospitalization, or ‘non-intensive’ chemotherapy. Although clinicians often perceive intensive chemotherapy as more burdensome, studies comparing older patients’ quality of life (QOL) and psychological distress while receiving these treatments are lacking. Methods: We conducted a longitudinal study of older patients (≥ 60 years) newly diagnosed with AML receiving intensive (i.e. 7+3: cytarabine/anthracycline combination) or non-intensive (i.e., hypomethylating agents) chemotherapy at two tertiary care hospitals. We assessed patient’s QOL [Functional Assessment of Cancer Therapy-Leukemia], and psychological distress [Hospital Anxiety and Depression Scale [HADS]] at baseline and 2, 4, 8, 12, and 24 weeks after diagnosis. We compared the proportion of patients in each group reporting clinically significant depression or anxiety (HADS subscale cut off ≥ 7) and used mixed linear effects models to compare QOL and psychological distress longitudinally between groups. Results: We enrolled 75.2% (100/133) of eligible patients within 72 hours of initiating intensive (n = 50) or non-intensive (n = 50) chemotherapy. Baseline QOL, depression, or anxiety symptoms did not differ between the groups. At baseline, 33.33% (33/100) and 30% (30/100) of the overall cohort reported clinically significant depression and anxiety, respectively, with no differences between groups. At 4 weeks, 41.98% (34/81) of patients in the overall cohort reported clinically significant depression, with no differences between groups. In mixed linear effects models, there were no differences in QOL (β = -0.71, SE = 1.12, p = 0.527), depression (β = 0.24, SE = 0.20, p = 0.226), or anxiety (β = -0.16, SE = 0.19, p = 0.386) symptoms over all time points. Conclusions: Older patients with AML receiving intensive and non-intensive chemotherapy experience similar QOL and high rates of psychological distress. These findings underscore the need to develop supportive care interventions for older patients with AML, regardless of their initial treatment strategy.

A 61-year-old man was admitted to this hospital because of recurrent fevers and pulmonary infiltrates. He had been well until approximately 3.5 months earlier, when chills, fevers, and fatigue developed, followed by dyspnea, all of which persisted despite antimicrobial therapy. On admission, the patient had daily fever, with temperatures up to 38.9° C; the erythrocyte sedimentation rate was 94 mm per hour. Computed tomography of the chest showed interlobular septal thickening and hilar and subcarinal lymphadenopathy. Positron-emission tomography showed diffuse uptake in the lungs. A diagnostic procedure was performed.

Outcomes among older patients with acute lymphoblastic leukemia remain poor. This study sought to determine the efficacy of an intensified, multi-agent approach derived from a Dana-Farber consortium trial in younger adults for patients older than 50 years (trial identifier NCT00973752).The primary endpoint was overall survival (OS) at 1 year. Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase. Imatinib was incorporated for Philadelphia chromosome-positive disease. After induction, the first consolidation incorporated clofarabine. Patients in remission could proceed to allogeneic hematopoietic cell transplantation (HCT) after induction and consolidation I. Those not receiving HCT went on to receive central nervous system, consolidation II, and continuation phases of treatment.Thirty patients were enrolled: 19 achieved a complete remission (CR) after induction and 1 achieved CR after consolidation I for a CR rate of 67%. Sixteen patients underwent HCT. The proportion surviving at 1 year was 63%, and this met the primary endpoint. The 2-year OS rate was 52% (n = 30), and the 2-year disease-free survival rate was 52% for patients achieving CR (n = 20). There was no survival advantage among those undergoing HCT. Therapy-related hyperbilirubinemia prompted adjustments and limitations to asparaginase dosing.Intensified chemotherapy can result in improved outcomes in comparison with historical data. Additional studies of similarly intensive regimens are warranted in this population. Cancer 2016;122:2379-2388. © 2016 American Cancer Society.

Health care utilization in older adults (age ≥60 years) with acute myeloid leukemia (AML) has not been well studied.We conducted a retrospective analysis of 330 consecutive older patients who were diagnosed with AML between May 1, 2005 and December 23, 2011, at 2 hospitals in Boston to examine their health care utilization and end-of-life care. Using multivariable logistic and linear regression models adjusting for covariates, we also compared health care utilization between patients who received intensive induction chemotherapy (n = 197; cytarabine/ anthracycline combination) versus nonintensive chemotherapy (n = 133; single-agent therapy).The median number of hospitalizations for the entire cohort was 4.2 (range, 1-18 hospitalizations). Patients who died spent a mean of 28.3% of their life after diagnosis in the hospital and 13.8% of their life attending outpatient clinic appointments. Although the majority of patients (87.9%) died during the 2-year follow-up period, a minority received palliative care (16.2%) or hospice (23.1%) services. Within 30 days of death, 84.5% of patients were hospitalized, and 61% died in the hospital. Among the patients who died, those who received intensive induction therapy (vs nonintensive therapy) spent 30% more of their life after diagnosis in the hospital (P .0001) and were less likely to receive hospice services (odds ratio, 0.45; P = .05).The current findings highlight the intensity of health care utilization among older patients with AML, regardless of treatment modality. Despite the poor prognosis, palliative care and hospice services are rarely used. Future work should study novel health care delivery models to optimize care throughout the course of illness and at the end of life.

We report a novel chromosomal translocation in AML, t(X;21)(q25-26;q22), resulting in a fusion transcript between two ETS domain family members, ELF4 (at Xq25) and ERG (at 21q22). ERG has been associated previously with other fusion partners, specifically FUS and EWSR1, and implicated in both AML and Ewing's sarcoma. RT-PCR analysis of RNA isolated from bone marrow samples from the patient demonstrates that the translocation occurs within intron 1 of ERG isoform 1 (ERG-1) and intron 2 of ELF4 resulting in an in-frame fusion joining exon 2 from ELF4 with exon 2 of ERG. This is the first reported case of an ELF4-ERG fusion and identification of the specific ERG exon involved in the fusion that differentiates ERG isoforms. In addition, this case also directly implicates a new role for ELF4 in cancer.

A 46-year-old woman had rapid onset of ascites, right upper abdominal discomfort, nausea, and vomiting. The serum–ascites albumin gradient was 1.2 g per deciliter. Venography demonstrated narrowing of the intrahepatic portion of the inferior vena cava; hepatic veins could not be visualized. Additional diagnostic procedures were performed.

The Cancer and Leukemia Group B (CALGB) study 9222 tested the hypothesis that treatment intensification of acute myeloid leukemia (AML) in first remission with multiple chemotherapy agents is superior to high-dose cytarabine (HiDAC) alone. We enrolled 474 patients younger than 60 years old with untreated de novo AML. Daunorubicin and cytarabine resulted in complete remission (CR) in 342 patients (72%), and 309 of these patients were randomized to receive one of 2 different intensification regimens. The first regimen consisted of 3 courses of HiDAC. The second regimen consisted of one course of HiDAC, a second course with etoposide and cyclophosphamide, and a third course with diaziquone and mitoxantrone. After a median follow-up time of 8.3 years, the median survival for all randomized patients was 2.8 years (95% CI, 1.9-6.8 years). There was no difference in disease-free survival (DFS) between the 2 regimens (P = .66). The median DFS was 1.1 years (95% CI, 0.9-1.7 years) for patients receiving HiDAC and 1.0 year (95% CI, 0.9-1.3 years) for those receiving multiagent chemotherapy. Cytogenetics was the only pretreatment characteristic prognostic for DFS, but there was no evidence of a differential treatment effect within cytogenetic risk groups. Toxicity was greater with multiagent chemotherapy. These 2 postremission regimens produced similar outcomes.

DNA methyltransferase inhibitors (DNMTis) have been shown to alter the natural history of MDS and reduce related complications; however, many patients do not respond to DNMTi therapy or progress with limited effective secondary options. Therefore, the ability to preselect which patients are most likely to respond to DNMTis would be useful in personalizing MDS therapy. Earlier reports noted a trend toward improved response to therapy in the presence of somatic TET2 mutations (Bejar et al, 2014), and lower response rates in patients with mutations in DNMT3A (Ley et al, 2010). Treatment with the DNMTi decitabine (DAC) requires 5 daily parenteral doses every month administered in the clinic. An orally administered DNMTi provides convenience with the potential for improved compliance, and allows for exploration of different extended dosing schedules which could produce alternative methylation of the genome and improve clinical response. DAC is not readily orally bioavailable due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDA inhibitor, is orally bioavailable with an excellent safety profile in preclinical models. ASTX727 is a combination of E7727 and DAC, and has completed phase 1 dose escalation of 44 MDS or CMML patients in which pharmacokinetic (PK) and pharmacodynamic (PD) parameters of DAC were replicated with the oral agent. During the dose escalation portion of the Phase 1 trial of ASTX727, bone marrow aspirates were obtained pre- and post- treatment from 28 patients (13 clinical responders), and genomic DNA from marrow cells was isolated for next-generation sequencing (NGS) with a panel of 37 myeloid neoplasia-associated genes. Consistent with previous reports, DNMT3A mutations were associated with poor response to ASTX727 (all 4 carriers failed therapy, P = 0.028). Conversely, of the 10 patients with TET2 mutations, a majority responded to treatment (6/10, P=0.444). ASXL1 mutations showed a complex combinatorial effect, as all three ASXL1-mutated patients with BCOR mutations, regardless of International Prognostic Scoring System (IPSS) risk category, were non-responders while all 3 patients ASXL1 who also carried a TET2 mutation responded. ASTX727 is an oral DNMTi that revealed responses in this dose escalation Phase I study exhibiting a similar pharmacokinetic profile and achieving AUC range of IV DAC. As previously observed with DAC, ASTX727 may lead to improved responses in patients with specific gene mutations. This work shows preliminary effects on mutational burden and allele frequency concurrent with activity of ASTX727. Further analyses of patients treated at the RP2D in the Phase 2 trial are ongoing. Citation Format: Haley E. Ramsey, Shilin Zhao, Yaomin Xu, Olatoyosi Otoyosi, Philip Amrein, Amy Dezern, Laura Michaelis, David P. Steensma, Stefan Faderl, Guillermo Garcia-Manero, James Lowder, Pietro Taverna, Michael R. Savona. Genetic correlations with clinical response to ASTX727 in patients with myelodysplastic syndromes (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2776. doi:10.1158/1538-7445.AM2017-2776

e18509 Background: Changes in the subclonal composition of AML may occur after diagnosis and be a mechanism of relapse. Cytogenetic changes between diagnosis and relapse may reveal evolution in clonal composition. We sought to determine whether evolution of patient cytogenetics impacts the response to salvage chemotherapy among AML patients who relapse after first remission. Methods: We identified adults with relapsed AML between 2001-2015. Studied patients received induction at diagnosis, achieved remission, relapsed, and received intensive salvage. APL and primary refractory AML were excluded. We identified cytogenetic abnormalities at relapse, and any clonal changes from diagnosis (gain/loss/no change). Associations with CR2 were analyzed by Fisher’s exact test. OS was from salvage therapy to death or censored at last known alive, with Kaplan Meier estimates. Results: 69 patients (median 54 yo, 58% male) received salvage therapy for relapsed AML. Most (81%) had de novoAML. Patients had favorable (7%), intermediate (70%), and adverse risk (23%) cytogenetics at diagnosis; 51% were normal karyotype. 94% received 7+3-based induction. 42% underwent allo-HCT in CR1. Salvage included 7+3 (n = 22), MEC (n = 36), HiDAC (n = 4), or other regimens (n = 7). Median time from CR1 to relapse was 10 mo (IQR 5, 18). At relapse, 29 patients (42%) gained cytogenetic abnormalities, 8 (12%) lost abnormalities, and 31 (45%) were unchanged. The most common acquired abnormalities involved chromosomes 7, 11, or 17 (each n = 6). 55% achieved CR2/CRi2 (CR2 w/ chromosome gain 48%, loss 38%, no change 65%). Longer CR1 duration was associated with greater likelihood of achieving CR2/CRi2 (p = 0.003). Accounting for CR1 duration, cytogenetic evolution from diagnosis to relapse was not significantly associated with CR2. Improved OS was seen with non-adverse diagnosis cytogenetics (p = 0.0003), longer CR1 (p = 0.035), and transplant in CR1 (p = 0.04). Conclusions: Although AML evolution frequently occurs between diagnosis and relapse (54% of this cohort had cytogenetic changes at relapse), this did not impact CR2 or overall survival. Rather, duration of CR1, likely a surrogate for depth of remission, significantly impacted outcomes.

Acute myeloid leukemia (AML) is a relatively resistant myeloid neoplasm commonly occurring in older patients (median age at diagnosis is 67 years).(1) AML outcomes are heterogeneous, with cure rates ranging from essentially zero in subsets of older patients to 80% in younger patients with favorable disease features.(2) Among various risk factors, karyotype is an important independent risk factor and is used to divide AML into good, intermediate and poor prognostic groups.(3, 4) The normal karyotype group is considered to be at intermediate risk and constitutes approximately 40% of patients with AML. However, even these patients have a heterogeneous outcome, with OS rates ranging from 24% to 42%. This group may be further stratified according to the presence or absence of mutations or expression levels of various molecular markers. (5, 6) FLT3ITD represents a segmental duplication within the juxtamembrane domain of FLT3 receptor and is found in 30–40% of CN-AML patients.(8) FLT3ITD is associated with monocytoid differentiation (FAB M5), higher white blood cell counts, increased serum lactate dehydrogenase, and higher peripheral and bone marrow blasts compared to wild-type FLT3 (wt FLT3) CN-AML patients.(9, 10) Patients with this mutation have similar complete remission (CR) rates but significantly increased relapse rates and a reduced OS as compared to patients with wt FLT3.(9–11) It has been further identified that the allelic ratio of mutant:wt transcripts impacts prognosis.(8, 10, 12–14) The length of the duplicated fragment and its specific location within FLT3 may also affect prognosis.(13, 15–17) Overall, CN-AML patients with a FLT3ITD mutation have an inferior prognosis compared to those with a wtFLT3. There is considerable debate over the best postremission treatment for FLT3ITD CN-AML patients.(18, 19) Another mutation, FLT3TKD, is a point mutation in the tyrosine kinase domain of the receptor and is found in approximately 10% of all CN-AML patients.(8) Similar to patients with FLT3ITD mutations, patients with FLT3TKD also have an elevated white blood cell count at presentation. However, the prognostic significance of TKD mutations is unclear.(9–11, 22–24) We analyzed patients with CN-AML and mutated FLT3 to determine the relationship between different postremission therapies and outcome. Our study includes all consecutively treated patients at our institutions who consented for determination of their FLT3 mutation status at diagnosis on a research study. The choice of post-remission therapy was not randomized but instead reflects the availability of open protocols and physician and patient preference. There were a total of 37 patients who were below the age of 60 years at diagnosis and had a normal karyotype with a FLT3ITD. Treatment histories of these patients are described in supplemental material (Fig S1). Patients who were positive for both the ITD and TKD mutation were included in the ITD group (n=7) because these individuals have similar outcomes as those with an isolated ITD mutation.(23, 27) The remission frequency for this patient population was 81.1% (30/37). There were 19 newly diagnosed AML patients with an isolated TKD mutation who were under the age of 60 and had a normal karyotype. Their treatment histories are shown in Supplemental Figure 2 (Fig S2). The CR frequency for this group was 89.5% (17/19). Excluded from our research question were 4/37 patients with FLT3ITD and 1/19 with FLT3TKD who received allogeneic SCT in CR1. However, we included patients who received an allogeneic SCT after first relapse (ITD: n=5; TKD: n=3). Time dependent covariate analysis indicated that receiving an allogeneic SCT after relapse did not significantly improve OS (p=0.62 for the ITD group and 0.83 for the entire cohort of patients; there were too few patients in the TKD group for this analysis to be conducted). Patient characteristics such as age at diagnosis, time to CR1, WBC at diagnosis and gender are in presented in Table 1. These features were balanced between those who were assigned to autologous SCT or consolidation chemotherapy in both ITD and TKD patient groups. Also, there was no significant difference in the distribution of allelic ratio and ITD length within the two treatment groups for ITD patients (p=.22 and .2, respectively). We then studied the relationship between baseline characteristics and clinical outcome and we found that among the characteristics listed in Table 1, only female gender was associated with a better DFS in patients with an isolated TKD mutation (p=.03). Table 1 Patient characteristics for ITD and TKD positive patients who initiated autologous SCT or consolidation chemotherapy. P value corresponds to comparisons within each type of mutation and not across FLT3 mutation types. We also found that an allelic ratio of >.2 was associated with a worse DFS and OS in ITD mutation positive patients who had initiated postremission autologous SCT or chemotherapy (n=21) (p=0.01 and 0.04). A value of 0.2 was determined as the optimal cut point by recursive partitioning analysis. The median length of the ITD in patients who initiated postremission autologous SCT or chemotherapy was 33bps (n=21) (Range=17–210). For patients with more than one mutation (n=5), the length of the most dominant mutation was chosen for analysis. In our study, the ITD length was not associated with DFS or OS. No other variable was noted to influence DFS or OS. We next analyzed the survival of patients with an isolated TKD mutation according to type of postremission therapy. For the 7 patients who initiated autologous SCT compared to the 9 patients who initiated consolidation chemotherapy, there was no significant difference in DFS or OS (p=0.97 and 0.082, respectively). Similarly, there was no significant difference in DFS or OS for patients who received a stem cell infusion or at least 3 cycles of consolidation chemotherapy (n=6 and 8, respectively; p=0.78 and 0.25, respectively). On the other hand, patients with an ITD mutation who initiated autologous SCT (n=10) had an improved DFS compared to those who initiated consolidation chemotherapy (n=11) (p=0.05) (Figure IA), however there was no difference in OS (p=.27) (Figure IB). Since some patients in each cohort (n=2 for autologous SCT and n=2 for consolidation chemotherapy) did not complete the initiated postremission therapy, defined as having received infusion of stem cells or at least 3 cycles of chemotherapy, respectively, we then compared the survival in patients who had completed their postremission therapy as defined above. Again, we found that autologous SCT (n=8) was significantly associated with an improved DFS compared to consolidation chemotherapy (n=9) (p=.03) while no significant difference in OS was observed (p=.19). Figure 1 A. DFS in months of patients with FLT3R ITD according to type of postremission therapy initiated Lastly we compared the survival outcomes of patients with ITD versus TKD who achieved CR and progressed to postremission therapy, excluding those who underwent allogeneic SCT in CR1. Patients with an isolated TKD mutation (n=16) had a significantly longer DFS and OS compared to patients with ITD (n=21) (p=.031 and .014). In summary, we analyzed the outcome of AML patients under 60 years with normal cytogenetics and FLT3 mutations according to the type of postremission therapy they initiated or received. Younger adults with ITD who initiated or received autologous SCT had an improved DFS compared to consolidation chemotherapy. OS, however, was not different for the two treatment modalities. For patients with isolated TKD, there was no difference in DFS or OS of patients who received autologous SCT versus consolidation chemotherapy. There is considerable debate about the optimal postremission therapy for CN-AML patients with a FLT3ITD mutation. Current options vary among allogeneic SCT, autologous SCT, and/or chemotherapy along with use of novel FLT3R inhibitors. In general, comparisons of autologous SCT and chemotherapy have not shown a clear difference in outcome when all AML patients are included. The potential benefit of autologous SCT in AML subgroups has not been extensively studied. Yoshimoto et al., in a retrospective analysis, demonstrated a similar DFS and OS for patients with a wtFLT3 versus a FLT3ITD who underwent an autologous SCT in CR1.(28) Bornhauser et al. also noted a decrease in probability of relapse and an improvement in OS for patients with FLT3ITD who received an autologous SCT in CR1 compared to those receiving chemotherapy alone.(19) In contrast, Schlenk et al. found no difference in relapse free survival and OS between normal cytogenetic patients receiving autologous SCT or conventional consolidation chemotherapy in both FLT3ITD and wt FLT3 patient groups.(18) Our data raise the question as to whether autologous SCT may be considered over consolidation chemotherapy for patients with ITD who are not undergoing allogeneic SCT or therapy with a FLT3 inhibitor.

Isolated myeloid sarcoma (MS) is a rare extramedullary presentation of acute myeloid leukemia (AML). Little is known about MS outcomes due to its rarity. A population-based analysis of MS using the Survival, Epidemiology, and End Results (SEER) database was performed. We identified 345 patients, aged 15 or older, diagnosed with isolated MS between 1973 and 2010. Overall survival (OS) was calculated and compared between MS and non-MS AML using the log-rank test. Survival was also evaluated based upon the primary site of disease presentation. The 3-year survival rate for MS (0.319; 95% confidence interval [CI]: 0.267-0.371) was greater than for non-MS AML (0.172; 95% CI: 0.168-0.175). There was variation in survival based on the site of involvement. The survival rates for isolated MS involving the pelvis/genitourinary organs, eyes/gonads and gastrointestinal mucosa appeared to be slightly improved when compared to primary sites of soft tissues, lymphatic/hematopoietic tissues or nervous system.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.

Introduction: Myelodysplastic syndromes (MDS) comprise a broad spectrum of hematologic malignancies with varying clinical courses; although most deaths are attributed to MDS, many patients will die of other attributable causes, independent of or potentially augmented by their underlying cancer. Cardiovascular (CV) disease is a frequently attributed cause of death in these patients, and may be influenced by CV care patterns in a patient's county of residence. Patients who live in counties with worse CV outcomes may be at greater risk of CV complications and death. We sought to determine whether regional quality of CV care in the US, measured by the rate of CV death in a county, impacts the cumulative incidence of death attributed to CV disease among MDS patients. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database from the National Cancer Institute to identify patients, age 15 and older, with a new diagnosis of MDS between 2001 and 2011. We identified 29,571 patients with a known age at diagnosis and follow-up, for whom MDS was the first cancer diagnosed in SEER. We grouped patients into lower risk disease (RA, RT, RN, and RARS), intermediate risk disease (MDS-unclassified, del(5q), RCMD, and t-MDS) and higher risk disease (RAEB and RAEB-T) according to SEER classifications. The incidence of a given cause of death (COD) was estimated by the cumulative incidence method identifying each COD as competing risks using R statistical software, and tested using the Gray test. We identified population rates of CV-specific mortality, according to the National Center for Health Statistics and available through SEER*Stat, in all counties with at least one MDS diagnosis over the study period. If the rate of death due to cardiovascular disease in a county was below the 25th percentile, then the CV performance was considered "good", if above the 75th percentile then the CV performance was considered "poor", and all others were considered "intermediate." Patients with MDS were grouped into a county CV performance quartile according to the rate of CV death in that county at the time of diagnosis. Results: The median age at diagnosis was 76 years (range 15-109) and the patients were 54% male. Patients were divided among lower risk (21%), intermediate risk (66%), and higher risk MDS (13%). Cause of death was reported for 29,344 patients. 602 counties had 1 diagnosis of MDS between 2001 and 2011, 599 of which reported overall CV mortality rates. A total of 15,856 MDS patients (54%) lived in counties with good CV performance (less than or equal to the 25th percentile of CV mortality) during the study period, while 11,845 (40%) lived in counties with intermediate CV performance, and 1817 (6%) lived in poor CV performance counties. MDS patients living in poor CV performance counties had a cumulative incidence of death attributed to cardiovascular disease of 7.2% at 12 months, compared to 4.8% and 5.1% among intermediate and good CV performance counties, respectively (p=0.0001). Death attributed to MDS was 15.7%, 15.6%, and 14.5% at 12 months for patients living in good, intermediate, and poor CV performance counties, respectively (Table 1). When looking specifically at MDS risk groups, it appeared that county CV performance had a greater impact on patients with intermediate and higher risk MDS (Table 1). Patients with higher risk MDS living in poor CV performance counties had a 12-month cumulative incidence of death due to CV disease of 9.3% compared to 4.2% and 3.6% in good and intermediate CV performance counties (p Conclusions: Most MDS patients live in counties with good CV performance; MDS patients living in counties with higher cardiovascular mortality have higher rates of death attributed to cardiovascular disease than do MDS patients living in intermediate or low cardiovascular mortality regions, while death attributed to MDS or other causes is relatively stable. This is more apparent among patients with higher risk MDS. These findings suggest that cardiovascular disease may be a modifiable risk factor for MDS patients. Table 12-Month Cumulative Incidence of Death due to MDS, CAD, and other causes. Table. 12-Month Cumulative Incidence of Death due to MDS, CAD, and other causes. Figure Cause of Death According to County Cardiovascular Performance. Figure. Cause of Death According to County Cardiovascular Performance. Disclosures Hobbs: Incyte: Other: participation in advisory board; Agios: Other: participation in advisory board. Fathi:Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Bexalata: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation.

Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate 1 and 2 (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs) decitabine (DAC) and azacitidine (AZA). Treatment requires 5 or 7 daily parenteral doses every month while the patient is benefitting. An oral HMA taken at home would provide patient convenience, and potentially enhance adherence to treatment particularly for long-term responders. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the final results of a Phase 1 study including an extension arm of a PK-guided first in human dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved daily dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Intrapatient dose escalation was permitted. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: 43 patients were treated in 5 cohorts of 6 patients each plus a 13 patient expansion of cohort 5. The median age was 71.5 years (range 59-86), 30/43 (70%) were male, and median time from diagnosis was 273 days (range 5-3518). Prior therapies had been administered to 22/43 (51%) patients including 20 who had received prior HMA. The AUC for IV DAC 20 mg/m2 in all patients (n=43) had a mean (CV) of 171(37%) ng*hr/mL. The Cmax for IV DAC 20 mg/m2 had a mean (CV) of 179(36%) ng/mL. Doses of each component of ASTX727 were escalated as shown in Table 1. E7727 was escalated first from 40 to 100 mg in cohorts 1 to 3 then kept constant at cohorts 4 to 6. DAC doses were kept constant at 20 mg in cohorts 1 to 3 then escalated to 40 mg at cohort 4 and de-escalated to 30 mg at cohort 5. Dose dependent increases in AUC and Cmax occurred with escalating doses. DAC AUC values after oral ASTX727 approached then exceeded IV at 149% by cohort 4. DAC Cmax values after oral ASTX727 never exceeded IV in any Cohort. Mean % LINE-1 demethylation on cycle 1 Day 8±SE increased with dose escalation reaching 12.8%±3.8 by cohort 4. Lower DAC AUC and Cmax were observed after lowering the oral DAC dose from 40 to 30 mg in cohort 5 as shown in Table 1. One patient in cohort 4 had a dose limiting toxicity of thrombocytopenia and no Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common ≥ Grade 3 AEs regardless of relationship to the drug were thrombocytopenia (36%), anemia (30%), neutropenia (27%), and febrile neutropenia (21%). No drug-related Grade ≥ 3 gastrointestinal AEs were reported. A median of 5 cycles (range 1-23) were administered, 11 patients remain on therapy, and 14 (32%) have experienced objective clinical responses so far, including 5 Complete Response (CR), 4 marrow CR, and 5 Hematologic Improvement. Of 23 patients initially RBC dependent, 6 (26%), became independent and of 6 who were platelet dependent, 2(33%) became independent. Conclusions: ASTX727 (the combination of E7727 and DAC administered PO concomitantly) achieved the primary PK objective of emulating IV DAC 20 mg/m2 AUC levels with a similar safety profile. Day 8 LINE-1 demethylation in Cohort 4, overall clinical response and transfusion independence rates are consistent with those historically reported following DAC 20 mg/m2 IV for 5 days, even though 47% had received prior HMA therapy. ASTX727 has now proceeded to a randomized phase 2 study comparing IV DAC 20 mg/m2 IV daily for 5 days to oral ASTX727 at the doses of 35 mg DAC and 100 mg E7727 daily for 5 days in Int or HR MDS and CMML patients. Disclosures Odenike: Geron: Research Funding; Suneisis: 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; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steensma:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Ariad: Equity Ownership; Genoptix: Consultancy; Millenium/Takeda: Consultancy. Michaelis:Incyte: Honoraria; Pfizer: Equity Ownership; Celgene: Honoraria, Speakers Bureau. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Zhang:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) of FLT3, MET, AXL, VEGFR, and KIT, all of which are implicated in the pathogenesis of acute myeloid leukemia (AML). Cabozantinib has been studied in clinical trials of solid tumors, and is FDA approved for use in medullary thyroid and renal cell carcinoma. Despite multiple relevant targets, cabozantinib has not been previously studied in AML. Given up-regulation of these key enzymes and related pathways in AML, we sought to assess the safety and tolerability of cabozantinib in this population. The primary objective of this phase I, 3+3 cohort dose-escalation study was to define the maximum tolerated dose (MTD) of cabozantinib in patients with AML. Eligibility included adults ≥ age 18, with relapsed or refractory (R/R) AML, or those aged ≥ 70, with new diagnosed AML but ineligible for or declining conventional therapy. Study treatment required a white blood cell count (WBC) of < 30,000/mm3, but concurrent treatment with hydroxyurea was allowed to control WBC during the first 15 days of cycle 1. The first dose level was 40MG by mouth daily (QD), a dose previously demonstrated to be well-tolerated in solid tumor malignancies. Cabozantinib was administered in 28 day cycles, and dose escalation occurred via 3 cohorts (40MG QD, 60MG QD, 80MG QD). Escalation to each successive dose level was guided by incidence of dose limiting toxicity (DLT) during cycle 1 of study treatment. Pharmacodynamic evaluation of serial plasma samples obtained from patients, by use of a plasma inhibitory assay (PIA), was used to assess FLT3 inhibitory activity in FLT3-ITDcell lines. Response was determined by bone marrow biopsy after the first cycle of treatment, and those achieving complete or partial remission, or with stable disease and clinical benefit, could continue on study until disease progression, intolerable toxicity, or upon receipt of 12 cycles. 18 patients were enrolled on study. The median age was 68 (range 27-85); 12 (67%) were male, and 14 (78%) were Caucasian. FLT3-ITD mutations were detected in 5 (23%) patients, and NPM1 mutations in none. 16 patients (89%) had R/R AML, and 2 patients (11%) had newly diagnosed disease. The majority (75%) of those with R/R AML had been treated with two or more lines of prior treatment. 3 patients were enrolled at the first dose level (40MG QD), of whom one experienced >G3 transaminitis, thought unrelated to cabozantinib, but could not be dosed for this reason and was therefore replaced. No DLTs were detected at the first dose level among the 4 studied patients. However, two of the three patients enrolled at the second dose level (60MG QD) experienced DLT, one with grade 3 pancreatitis and the other with grade 3 transaminitis. Three patients were then enrolled at the next lower level, dose level 1 (40MG QD), of whom two could not complete the DLT period, one because of disease progression and the other due to an infected aortic ulceration unrelated to study treatment. These two patients were replaced, and no additional DLTs were noted. 40MG daily was therefore determined to be the MTD, and 6 patients were subsequently treated in an expansion cohort at this dose. Additional ≥ grade 2 toxicities, possibly or probably related to cabozantinib, each affected 3 or less patients, and included fatigue, nausea, anorexia, constipation, oral mucositis, palmar-plantar erythrodysesthesia, transaminitis, and electrolyte imbalance. Fifteen patients could be assessed for response on study. No patients had a marrow response per formal criteria. Four patients had a reduction in peripheral blasts during treatment, of whom 2 transiently cleared their circulating blasts (one with FLT3-ITD). One patient experienced a reduction in marrow blasts, and one had stable marrow disease. FLT3 inhibitory activity of serially collected patient plasma samples, as determined by the ex vivo PIA, consistently revealed potent and sustained inhibition of FLT3 auto-phosphorylation in FLT3-ITDmutant cell lines by day 8 of cycle 1. Cabozantinib, a multi-targeted TKI, is well-tolerated in patients with AML at the MTD of 40 MG daily. In this molecularly heterogeneous, heavily pre-treated population of AML patients, clinical response to cabozantinib monotherapy was limited. However, we found that cabozantinib inhibits FLT3-ITD tyrosine kinase in a potent and sustained fashion. Additional clinical study of cabozantinib among patients with FLT3 mutant AML is therefore warranted. Disclosures Fathi: Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation. Levis:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding. Avigan:Astex: Research Funding; DCPrime: Research Funding. Hobbs:Constellation: Other: Advisory Board participation; Incyte: Other: Advisory Board participation.

Activation of MAPK signaling is characteristic of many cancers, and approximately 15% of AML patients carry activating RAS mutations. The PI3K pathway is also constitutively activated in AML. Both pathways interact with each other extensively and provide compensatory signaling when one pathway is inhibited. It has been demonstrated in vitro that concurrent inhibition of both pathways is effective in blocking the proliferation of AML cell lines through an immediate decrease in pAkt and pErk, leading to inhibition of pS6 (Gritsman et al, J Clin Invest, 2014, 124(4):1794-1809). The combination of alpelisib (BYL-719), which inhibits PI3K (p110alpha), and binimetinib (MEK-162), which inhibits MEK (MAPK pathway), was tested in various tumor types in the Phase Ib Clinical Trial CMEK162x2109. We present here the clinical data and correlative phosphoprotein analysis of 6 patients with relapsed refractory RAS-mutated AML treated at Massachusetts General Hospital on Extension Arm 4A of this trial. Entry to this trial was restricted to adult patients with RAS-mutated AML previously treated with 1 or 2 prior chemotherapy regimens or for whom there was no known effective therapy. Patients received 200mg QD of alpelisib and 45mg BID of binimetinib concurrently and continuously with adjustments for toxicities. Hematologic toxicity could not be determined in these patients with active AML causing myelosuppression. There were responses in blood and/or bone marrow (BM) in 3 patients, but none made partial response criteria by IWG guidelines, mainly due to platelet counts 50% reduction in a third patient. A rise in absolute neutrophil count was seen in 3 patients, 2 from below 100/ul to above 500/ul, and in 1 from 5,320/ul to 12,797/ul during the first month. BM partial responses were seen in 2 patients, with blast percentages dropping from 39% to 10% in 1 patient and from 12% to 5% in another. We analyzed the effects of this drug combination on signaling targets by collecting peripheral blood samples on day 1 pre-treatment and at 6 and 24 hours post-initiation of treatment. In 4 patients, we performed analysis of the phosphorylation of Akt, ribosomal protein S6, Erk, STAT5, and STAT3 on timed peripheral blood samples by immunoblotting. In all 4 cases at baseline, pAkt, pErk, and pS6 were detectable, while pSTAT5 and pSTAT3 levels were variable. In 3 of 4 cases, we observed a transient decrease in pAkt at 6 hours, but then a rebound at 24 hours. In 3 of 4 cases, we observed a lack of sustained pS6 inhibition. We observed sustained pErk inhibition at 24 hours in 2 cases. One patient who had blood blast clearance, improvement in ANC, and a drop in bone marrow blasts, showed strong inhibition of pAkt and pERK at 6 hours, although pS6 did not decrease. In another case we performed phospho-flow cytometry on timed whole blood samples. We observed an increase in pAkt, pS6, and pErk from baseline at 24 hours, both in CD34+38+blasts, and in the primitive CD34+38- cells. This second patient showed no clinical benefit from the treatment in terms of blood blast count, ANC, or platelets. We also performed immunohistochemistry for pS6, pErk, pAkt, pSTAT5, pSTAT3, p-eIF4E, and Caspase 3 on BM sections obtained at diagnosis and at one month and two months post-initiation of treatment, when available. These studies generally showed either persistence or an increase in the pS6 and p-eIF4E signals, both indicators of mTORC1 activity, in post-treatment BM samples. Levels of pAkt, pErk, pSTAT5 and pSTAT3 were highly variable in the post-treatment bone marrow samples. In conclusion, we demonstrated some initial target inhibition with the concurrent use of alpelisib and binimetinib in a subset of patients. However, inhibition of late downstream targets was not sufficiently sustained to achieve consistent clinical benefit in our patients with RAS-mutated AML. While the strategy of concurrent inhibition of various critical signaling pathways remains interesting, sustained inhibition of downstream signaling may require a different dosing schedule of the two drugs. Given the incomplete inhibition of mTORC1 targets pS6 and p-eIF4E in most cases, the addition of a third agent to inhibit pathways causing cross-activation downstream of mTORC1 may be required. Disclosures Weinstock: Novartis: Consultancy, Research Funding. Fathi:Bexalata: Other: Advisory Board participation; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Agios Pharmaceuticals: Other: Advisory Board participation.

BACKGROUND The objective of this Phase II study was to define the response rate, safety profile, and toxicity of oral uracil and ftorafur (UFT) with leucovorin (UFT/LV) as a palliative treatment for patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS Patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group performance status < 2 and adequate organ function were enrolled in an institutional review board-approved trial. Prior induction or adjuvant chemotherapy was permitted provided 6 months had elapsed since the last chemotherapy. Patients were treated with UFT 300 mg/m2 per day and leucovorin 90 mg per day administered in three doses daily for 28 days followed by a 7-day break for a 35-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS One hundred six cycles of UFT/LV had been administered to 42 patients as of January 1, 2000. The most common toxicities, in descending order of incidence, were anemia, pain, fatigue, diarrhea, nausea, mucositis, and anorexia. Clinically significant toxicities attributable to UFT/ LV were primarily gastrointestinal. On an intent-to-treat basis, three patients (7%) achieved a complete response, and six patients (14%) achieved a partial response. The overall response rate was 21% (95% confidence interval, 10–37%). CONCLUSIONS UFT/LV therapy is feasible in this patient population and is generally well tolerated. Response rates are similar to the rates expected with continuous-infusion 5-fluorouracil. UFT/LV should be studied further both alone and in combination therapy for patients with SCCHN. Cancer 2001;92:326–31. © 2001 American Cancer Society.

BACKGROUND Although chemotherapy can achieve a high rate of disease remission induction in patients with newly diagnosed acute myelogenous leukemia (AML), patients with recurrent or refractory AML generally have a poorer rate of response. This study assessed the utility of mitoxantrone and intermediate-dose cytarabine (Ara-C) in the treatment of patients with recurrent or refractory AML. METHODS Forty-seven patients with recurrent or refractory AML were treated with Ara-C, 0.5 gm/m2, intravenously (i.v.) every 12 hours × 12 doses on Days 1–6 and mitoxantrone, 5 mg/m2, i.v. on Days 1–5. RESULTS Twenty-nine of the 47 patients (62%) achieved a complete response. The median duration of disease remission was 112 days (range, 29 days–8 years). Of the 25 patients age ≥ 60 years, 19 (76%) had a complete disease remission and the median duration of disease remission in this group was 114 days (range, 33–370 days), although all patients subsequently developed a disease recurrence. The chemotherapy generally was well tolerated, with a mean duration of neutropenia of 31 days and a mean duration of thrombocytopenia of 33 days. Three patients died of infectious complications between 23–26 days after the initiation of chemotherapy, 1 patient died of sudden cardiac arrest 13 days after the initiation of chemotherapy, and 1 patient developed cutaneous desquamation. Three patients developed acute cerebellar dysfunction. CONCLUSIONS The use of mitoxantrone and Ara-C is effective in the treatment of patients with recurrent and refractory AML. The subgroup of patients age ≥ 60 years also had a high rate of disease remission induction with this regimen, and the regimen generally was well tolerated. Cancer 2000;88:2037–41. © 2000 American Cancer Society.

Newly diagnosed patients with acute myeloid leukemia (AML) were randomized to receive either 2.5 or 5 μg/kg/day of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) or a placebo administered subcutaneously after completion of chemotherapy. The study evaluated the toxicity of PEG-rHuMGDF and any effect on the duration of thrombocytopenia. Each of 35 patients under 60 years of age received the following therapy: 45 mg/m2 daunorubicin on days 1-3, 100 mg/m2cytarabine (ARA-C) for 7 days, and 2 gm/m2 high-dose ARA-C (HIDAC) for 6 doses on days 8-10. The 22 patients 60 years or older received standard daunorubicin and ARA-C without HIDAC. PEG-rHuMGDF was well tolerated, and no specific toxicities could be attributed to its use. There was no difference in the time to achieve a platelet count of at least 20 × 109/L among the 3 groups (median 28-30 days for patients less than 60 years old and 21-23 days for patients 60 years or older). Patients receiving PEG-rHuMGDF achieved higher platelet counts after remission. However there was no significant difference in the number of days on which platelet transfusions were administered among the 3 groups. The complete remission rate was 71% for patients less than 60 years and 64% for those 60 years or older, with no significant difference among the 3 groups. Postremission consolidation chemotherapy with either placebo or PEG-rHuMGDF was given to 28 patients beginning the day after completion of chemotherapy. There was no apparent difference in the time that was necessary to reach a platelet count of at least 20 or 50 × 109/L or more platelets or in the number of platelet transfusions received. In summary, PEG-rHuMGDF was well tolerated by patients receiving induction and consolidation therapy for AML; however, there was no effect on the duration of severe thrombocytopenia or the platelet transfusion requirement.

A phase II trial was conducted to determine which of the three possible two-drug combinations of diaziquone, etoposide and mitoxantrone was associated with the highest response rate in patients with relapsed or refractory acute myeloid leukemia (AML). Of the 167 patients (median age 55) with AML who entered the trial, 123 were in first relapse, 22 were in second relapse and 22 had failed to achieve complete remission (CR). CR rates were 30% for diaziquone and mitoxantrone, and 23% for the other two combinations (mitoxantrone/etoposide and diaziquone/etoposide), NS. Patients in first relapse had higher CR rates (40%) than other patients. Of the 166 patients who actually received treatment, 43 died before having either a CR or persistent leukemia. Non-hematologic toxicity was primarily mucosal with 24% of patients experiencing grade 3 or greater stomatitis on the two diaziquone arms, and 43% on the mitoxantrone/etoposide arm. The combination of diaziquone and mitoxantrone was selected for further testing in patients with AML.

Purpose. Chemotherapy has been tested extensively in conjunction with standard therapy in the treatment of head and neck cancer, primarily in the form of neoadjuvant chemotherapy, but few trials have shown a survival benefit. Although a few studies have suggested that adjuvant chemotherapy given after standard treatment may improve survival, to date these trials have been troubled by various problems in design and dosing. The purpose of our trial was to determine the feasibility of giving moderately intensive chemotherapy exclusively after standard therapy, and to determine whether survival appeared to be improved as measured against historical data. Methods. We used adjuvant chemotherapy in two groups of patients with squamous cell carcinoma of the head and neck: group A consisted of 46 patients with newly diagnosed stage III and IV disease, and group B consisted of 46 patients with relapsed disease having been treated with salvage surgery. In all patients, the intended adjuvant chemotherapy consisted of two cycles of combination cisplatin, bleomycin, and infusional 5-fluorouracil (5-FU) given three weeks apart, followed by four cycles of bolus methotrexate, 5-FU, and bleomycin given every two weeks. Results. In group A, the two-year survival was 72%. In group B, the two-year survival was 58%. Conclusion. Compared to the vast majority of similarly staged patients with head and neck cancer reported in the literature, the survival of our group seemed considerably better, suggesting that a definitive randomized study testing this schedule of adjuvant chemotherapy is warranted.

This study evaluated the effect of filgrastim (granulocyte colony-stimulating factor [G-CSF]) on the duration of granulocytopenia and thrombocytopenia after intensive consolidation therapy with diaziquone (AZQ) and mitroxantrone for patients less than 60 years of age with acute myeloid leukemia (AML) in complete remission. Patients less than 60 years of age with AML who achieved complete remission (CR) with daunorubicin and cytarabine induction therapy, were scheduled to receive three sequential courses of high-dose cytarabine, cyclophosphamide/etoposide, AZQ, and mitroxantrone in a pilot study to determine their tolerance of these three sequential consolidation regimens. The initial patients treated with AZQ and mitoxantrone experienced prolonged bone marrow suppression and, therefore, subsequent cohorts were treated with G-CSF, 5 μg/kg, beginning the day after completion of the third cycle of chemotherapy. There was a marked decrease in the duration of granulocytopenia less than 500/μL in two groups of patients receiving two different dose levels of AZQ and the same dose of mitoxantrone compared with patients not receiving the G-CSF. There was also a decrease in the need for hospitalization, as well as the duration of hospitalization. There was a trend towards shortening of the duration of thrombocytopenia, as well. The duration of complete remission and overall survival was similar in patients who received or did not receive G-CSF. G-CSF markedly shortened the duration of granulocytopenia in patients with AML receiving intensive postremission consolidation with AZQ and mitoxantrone. There was no adverse effect on CR duration or survival.

Pediatric lung transplantations (LTx) remains a small part of LTx performed worldwide. The majority of these Tx concerns young adolescents, transplantations in infants being anecdotic. We conducted a retrospective study of LTx in children and adolescents in one center in Paris from the beginning of the 90's to 2013.Data from Broussais then HEGP were collected retrospectively from 1990 to 2013: 380 LTx were reported in 368 patients including 111 LTx performed among children from 5 to 18 years of age (30%).One hundred and eleven patients received 121 LTx: 86 bilateral LTx, 13 combined lung-liver, 3 monopulmonary, 5 heart-lung and 4 combined heart-lung-liver Tx. Eighty-eight percent of the patients had cystic fibrosis. Median age was 14 years, weight 34 kg and height 144 cm. Median age of donors was 27 years, weight 60 kg and height 167 cm. Conditional survival for children was not different than adults: 72% at one year, 42% at 5 years, 37% at 10 years and 26% at 15 years. There was not overall early mortality after transplantation. Era graft survival was significantly higher after year 2000 (53% at 5 years vs 32% P=0.03).Lung transplantation among children under 18 years have similar outcome to those of adult patients.

Novel therapies for the treatment of acute myeloid leukemia are required to overcome disease resistance and to provide potentially less toxic therapies for older adults. Prior clinical trials involving patients with non-small cell lung cancer have demonstrated the safety and biologic activity of the administration of EGFR inhibitors in carefully selected patients. The potential efficacy of this approach in patients with acute myeloid leukemia is unknown. The effects of gefitinib on differentiation induction and cell viability in AML cell lines and primary patient AML cells were previously reported and cell viability was inhibited in a clinically achievable range. To determine if EGFR inhibitors would be therapeutically efficacious in advanced AML, we performed a phase II trial in which 18 patients with a median age of 72 (range, 57 to 84 years) were treated with gefitinib (750 mg orally daily). While there were no unexpected toxicities, no patients experienced an objective response, though one had stable disease lasting 16 months. We conclude that in spite of pre-clinical activity and anecdotal cases of response to EGFR inhibitors, routine use of the EGFR inhibitor gefitinib as a single agent for advanced AML is not appropriate.

Purpose: Previous evaluation of HER2 overexpression in salivary gland cancers indicated an incidence varying between 7 and 56%, with no clear difference among three histologically different subtypes. As part of a Phase II trial of trastuzumab for treatment of incurable salivary gland cancer, we screened 137 tumors for HER2 expression. Experimental Design: Unstained sections of paraffin-embedded tumor samples were stained with p185/HER2 receptor antibody. Tumors with moderate (2+) to strong (3+) complete membrane staining in at least 10% of the tumor cells were scored as positive for overexpression. Results: The overall frequency of overexpression for HER2 was 17% (23 of 137), whereas it was only 8% in the three most common histological subtypes screened. Overexpression was distinctly rare in the most common subtype screened, adenoid cystic carcinoma (4%, 3 of 70). Overexpression was very common in salivary duct cancers; 10 (83%) of 12 were positive for HER2. This observation is consistent with the typical high-grade histological features and aggressive behavior of this subtype as well as with its histogenetic similarity to breast cancer. Analysis based on histogenesis (intercalated duct versus excretory duct) indicated a higher frequency of overexpression in the latter (55%) than in the former (7%). Conclusions: Our overall results suggest that trastuzumab will not have a major role in treatment of salivary gland cancers of intercalated duct origin. Further systematic evaluation of trastuzumab in subtypes of excretory duct origin could be supported.

Resume • Objectif : Evaluer les effets hemodynamiques et respiratoires d'un immunosuppresseur par le muromonab CD3 (Orthoclone OKT3®) administre pendant les trois jours suivant la transplantation cardiaque, pour la prevention du rejet precoce de greffe. • Type d'etude : Etude clinique prospective. • Patients : Douze patients dont les resistances arterielles pulmonaires avant transplantation etaient inferieures a 400 dyn·s·cm −5 et dont les parametres hemodynamiques postoperatoires, en l'absence d'un traitement inotrope majeur, etaient stables depuis au moins 4 heures. • Methode : Patients, sous ventilation mecanique avec FiO 2 = 0,6 a j0, puis en ventilation spontanee, sous air enrichi en oxygene a j1 et j2, recevant isoprenaline 0,05 g·kg −1 ·min −1 et dopamine 3 g·kg −1 ·min −1 et dont le traitement immunosuppresseur comportait azathioprine 5 m·kg −1 a j0, puis 3 mg·kg −1 a j1 et j2, et methylprednisolone 720 mg a j0 et 240 mg a j1 et j2. L'OKT3 etait administre par voie i.v. a la dose de 5 mg toutes les 24h. Les variables hemodynamiques et respiratoires obtenues avant (=T0), puis 30 min (=T1) et 360 min (=T3) apres l'injection d'OKT3 a j0, j1 et j2. • Resultats : Aucune repercussion clinique ni radiologique n'a ete decelee. A T2 de j0, la frequence cardiaque s'est elevee et la PaO 2 ainsi que la SaO 2 ont diminue. Les autres parametres sont restes inchanges. A T1 de j1 et de j2, la PaO 2 a egalement diminue. Le shunt a augmente a j2 de pres de 3 %. • Conclusions : Dans les conditions de l'etude, l'administration d'OKT3 n'a eu qu'un retentissement modere sur l'hematose, surtout net a j2. Cette bonne tolerance peut etre attribuee d'une part a la selection des patients, exempts d'hypertension arterielle pulmonaire et, d'autre part aux fortes doses de corticoides administrees.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy generally associated with a poor prognosis. While many patients can achieve a complete remission with traditional induction ther...

Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs). Treatment with the HMAs decitabine (DAC) and azacitidine (AZA) requires 5 or 7 daily parenteral doses respectively every month with some patients remaining on treatment for extended periods. An orally administered HMA would provide significant patient convenience, potentially enhance adherence to treatment, and may allow exploring extended treatment schedules with lower doses of DAC. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the first Phase 1 results of a PK-guided FIH dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial with a 3+3 design. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. A data safety review committee evaluated safety, PK and PD on patients in each completed cohort and determined dosing for each component of ASTX727 at the next cohort. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: The Phase 1 portion of the trial completed dosing of 4 cohorts with 6 subjects each (24 subjects). The median age was 71 years (range 59-85), 15/24 (63%) were male, and median time from diagnosis was 307 days (range 5-3024). Prior therapies were administered to 10 patients including five who had received prior HMA. In cohorts 1-3 ASTX727 was given as a fixed oral DAC dose of 20 mg with escalating doses of oral E7727 at 40, 60, and 100 mg respectively. In cohort 4, the oral DAC dose was escalated to 40 mg while E7727 was kept at 100 mg. The Day 1 AUC for IV DAC 20 mg/m2 over all 4 cohorts had a mean (SD) value of 193(82) ng*hr/mL. After oral ASTX727 on Days 2-5, the mean DAC AUC as % of IV DAC AUC was 17, 19, 32, and 98% on Day 2 and 31, 41, 58 and 148% on Day 5, in cohorts 1-4 respectively (Figure). DAC AUC variability after oral ASTX727 was acceptable (CV% 35-53 across 4 cohorts). DAC Cmax values after oral ASTX727 approached IV (87%) in Cohort 4 on Day 5. Mean % LINE-1 demethylation on cycle 1 Day 8±SE was 6.8%±2.7; 8.6%±2.7; 9.5%±3.3; and 15.3%±3.4 from baseline for cohorts 1-4 respectively. No Dose Limiting Toxicities (DLTs) or Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common Grade ≥ 3 AEs regardless of relationship to the drug were thrombocytopenia (37.5%), anemia (33.3%), neutropenia (29.2%) and febrile neutropenia (16.7%). Twenty patients remain on therapy, and at least 5 so far have experienced objective clinical responses (including 1 Complete Response (CR), 1 marrow CR, 1 Partial Response and 2 Hematologic Improvement). Conclusions: ASTX727 (the combination of oral DAC and oral CDAi E7727 administered concomitantly) achieved the primary PK objective of reaching (at Day 2) or exceeding (at Day 5) IV DAC 20 mg/m2 AUC levels at the doses of 40 mg DAC and 100 mg E7727 with an excellent safety profile. Day 8 LINE-1 demethylation in Cohort 4 is consistent with that historically reported following DAC 20 mg/m2 IV for 5 days. Clinical responses have been observed. The trial will explore lower doses of oral DAC and will proceed to dose expansion followed by randomized phase 2 portion comparing IV DAC to oral ASTX727 in previously untreated Int or HR MDS and CMML patients. Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Astex Pharmaceuticals, Inc: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Faderl:JW Pharma: Consultancy; Karyopharm: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Astellas: Research Funding; Celator: Research Funding; Ambit: Research Funding; Onyx: Speakers Bureau; BMS: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Dua:Astex Pharmaceuticals, Inc.: Employment. Nawabi:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment.

Mutations in genes encoding the isocitrate dehydrogenase 1/2 (IDH 1/2) enzymes increase production of the oncometabolite 2-hydroxyglutarate (2HG), resulting in elevated 2HG in patients with IDH-mutant AML. This may allow for non-invasive diagnostic and predictive markers of disease; however, the optimal threshold of 2HG levels to predict IDH mutation status, or whether 2-HG measurements in different compartments are equally predictive, is unknown. We measured 2-HG levels in serum, urine, bone marrow aspirate, and bone marrow cell pellet to determine the optimal predictive value of 2HG levels for IDH mutations at AML diagnosis. Patients with newly diagnosed AML had prospective measurements of 2HG levels at diagnosis by liquid chromatography-tandem mass spectrometry in serum, urine, marrow aspirate, and marrow pellet samples. Patients analyzed had IDH1 R132 and IDH2 R140 and R172 testing. Hotspot mutational profiling was performed for AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, P53, and PTEN; patients were also tested for FLT3, NPM1, and CEBPA mutations. IDH1/2 mutant patients were compared to wildtype (WT) patients using a Wilcoxon rank sum, Fisher's exact, or Kruskal Wallis test, as appropriate. Performance characteristics of 2HG to predict the presence of IDH1/2 mutations were done using a recursive partitioning algorithm in R version 3.2.1, with the rpart package. 228 patients with newly diagnosed AML had 2HG levels in serum, urine, marrow aspirate, and marrow pellet samples. All patients had testing for IDH1 R132 and IDH2 R140 and R172 mutations. The patients were 56% male; 13 patients had APL, none with IDH mutations. IDH mutations were identified in 23% (n=52) of the cohort: IDH1 R132C (n=12), IDH2 R172 (n=9), and IDH2 R140Q (n=29), and 2 additional patients had mutations in both IDH1 R132 and IDH2 R140 (Table 1). The optimal test cut-off of 2HG to predict IDH status was 534.5 ng/mL in the serum (n=221), 16650 ng/mL in the urine (n=213), 2210 ng/mL in the marrow aspirate (n=190), and 1146 ng/2*10^6 cells in the pellet (n=159). Serum and pellet values had the greatest specificity for the presence of an IDH1/2 mutation (0.9882 and 1.000, respectively; Table 2). The positive predictive value of an elevated serum or pellet 2HG level at these cut-offs was 95.4% and 100%, given a 23% IDH mutation prevalence in this study population. The marrow aspirate had the greatest sensitivity (0.8837) and negative predictive value (96.6%). Urine 2HG levels were less sensitive than serum 2HG levels, although above the urine cut-off the specificity for IDH mutations was similar (Figure 1). 2HG levels in the serum, urine, and marrow can be used to identify IDH mutations in AML. Serum 2HG testing is an effective non-invasive mechanism to predict IDH1/2 mutation status. A serum cut-off of 534.5 ng/mL has a specificity of 0.9882 and, with an IDH mutation prevalence of 23%, was associated with a PPV of 0.9535.Table 1.Patient CharacteristicsNo IDH mutationIDH mutationTotalp-valueMale sex101 (57%)26 (50%)127 (56%)0.43Cytogenetics0.0002Favorable26 (15%)026 (12%)Intermediate95 (54%)41 (82%)136 (61%)Adverse52 (30%)9 (18%)61 (27%)Age (median, range)66 (20, 87)66.5 (41, 86)66 (20, 87)0.27WBC (median, range)5.35 (0.60, 315.4)3.65 (0.20, 333.2)5.25 (0.20, 333.2)0.33No IDH mutationIDH mutationNumber assessedp-valueNRAS27 (17%)9 (19%)2100.83KRAS16 (10%)0 (0%)2100.03TP5315 (9%)1 (2%)2100.13KIT2 (1%)1 (2%)2100.54FLT3ITD34 (20%)4 (8%)2180.06FLT3TKD10 (6%)2(4%)2180.74NPM129 (17%)15 (30%)2190.07CEBPA13 (13%)3 (10%)1021.002HG MeasurementsNo IDH mutationIDH mutationTotalSerum (ng/mL)79.5 [52,123] n=1701420 [675,2735] n=51101 [58,101] n=221Urine (ng/mL)3590 [2230,6220] n=16318300 [7260,59500] n=504330 [2450,8580] n=213Marrow aspirate (ng/mL)BQL [BQL,BQL] n=14718400 [4270,43100] n=43BQL [BQL,1430] n=190Pellet (1000 ng/2*10^6 cells)64 [BQL,169] n=1271420 [675,2735] N=32107 [BQL,500] n=159 Table 2. Test characteristics based on optimal 2HG cut-off, by compartment. Compartment 2HG cut-off Sensitivity Specificity 23% prevalence PPV NPV Serum 534.5 ng/mL 0.8039 0.9882 0.9535 0.9438 Urine 16650 ng/mL 0.5600 0.9877 0.9333 0.8798 Marrow Aspirate 2210 ng/mL 0.8837 0.9660 0.8837 0.9660 Marrow Pellet 1146 ng/2*10^6 cells 0.7813 1.000 1.000 0.9478 Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 2. Figure 2. Disclosures Chen: Bayer: Consultancy, Research Funding. Stone:Agios: Consultancy; Celator: Consultancy; Pfizer: Consultancy; Merck: Consultancy; AROG: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Juno: Consultancy; Novartis: Research Funding. Fathi:Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding.

Background The diagnosis of acute myeloid leukemia (AML) is associated with a poor prognosis, particularly for patients older than age 65 and those with relapsed or refractory disease. Little is known about the specific location where AML patients die and how disease status, therapeutic management, and symptoms influence the place of death. Methods We conducted a retrospective descriptive analysis of consecutive patients with AML who died at our institution between January 2007 and December 2012. In addition to place of death, the variables of interest included: disease status at death, previous transplant, prior chemotherapy, presence of a dedicated caregiver, gender, and age at diagnosis. Disease status was classified as: new diagnosis, active disease, relapsed, or in remission. A new diagnosis was defined as a diagnosis within the prior 30 days. Active disease was defined as disease beyond 30 days and without prior remission. Medical records were reviewed to identify whether palliative care service was consulted, and the range of symptoms reported during the last two weeks of life. Categorical variables were compared among groups using chi-square and continuous variables with the Kruskal Wallis test. Results We identified 166 patients with AML. The majority of study patients were white (90%) and male (55%) with a median age of 69 years (range 21-94 years). Disease was characterized as de novo AML (49%), therapy related (14%), secondary to antecedent myelodysplasia (29%) or other hematologic disease (8%). The median time from diagnosis to death was 5.5 months (range 0.7-50.4). The majority (82%) had active AML at time of death. Other causes of death included transplant related complications (8%), sepsis (4%), bleeding (2%), or other (4%) causes. Palliative care consultation occurred in 35% of the cases. The consults typically were late in the course of illness with the median time from initial consult to time of death of 8 days (range 0-122 days). Information on the location of death was available for 154 patients, of whom, 23 (15%) died in inpatient hospice, 41 (27%) at home, 48 (31%) died while hospitalized in a non-ICU bed and 42 (27%) died in either the Intensive Care Unit or Emergency Department (ED). Location of death was significantly associated with disease status at death (p< 0.0001, Figure 1), prior anthracycline/cytarabine based induction therapy (p=0.01), social support/dedicated caregiver (p=0.05), and age at diagnosis (p Conclusions The majority of AML patients are in a hospital setting at the time of death. Important factors for the location of death include age at diagnosis, disease status, social support and prior induction chemotherapy. Symptoms at the end of life included pain, delirium and bleeding. Palliative Care was not optimally utilized in the majority of cases. Interventions are needed to improve symptom management and health care utilization at the end of life for patients with AML. Figure 1. Figure 1. Disclosures Fathi: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Exelexis: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Ariad: Consultancy. Attar:Agios: Employment.

Background: The prognosis for patients with relapsed acute myeloid leukemia (AML) remains extremely poor. Standard reinduction regimens, such as mitoxantrone, etoposide, and ara-C (MEC), have been associated with complete remission rates in the 23 to 30% range. Lenalidomide (Len), an immunomodulatory drug, has efficacy in relapsed AML and has been shown to augment the effects of standard chemotherapies (anthracyclines and ara-C) in preclinical AML studies. These data prompted the current phase 1 study of Len in combination with MEC in pts with relapsed AML. Methods: The trial included pts (≥ 18 yrs) with relapsed or refractory AML. The primary objective was determination of the maximum tolerated dose (MTD) of Len when given in combination with MEC. Secondary objectives included safety, efficacy and time to count recovery. The study examined escalating doses (5-10 mg) of Len given daily for the first 14 days in combination with standard MEC doses of mitoxantrone (8 mg/m2/d), etoposide (100 mg/m2/d), and ara-C (1000 mg/m2/d) on days 4 through 8. Due to observations of prolonged count recovery, the Len dosing schedule was amended by reducing the duration of treatment to 10 days starting on Day 1. The dose of len was then re-escalated starting at 5 mg/d (5-10-25-50). A standard 3+3 dose-escalation design was used. Dose limiting toxicity was defined as Grade IV rash or Grade IV neuropathy during the first 28 day period, or delayed neutrophil (ANC Results: A total of 33 pts have been enrolled in the study (25 escalation phase [5 mg days 1-14, n=3; 10 mg days 1-14, n=6; 5 mg days 1-10, n=3; 10 mg days 1-10, n=3; 25 mg days 1-10, n=3; 50 mg days 1-10, n=6] and 8 expansion phase pts at 50 mg/d days 1-10). One patient was enrolled, found to be ineligible, and not treated. The median age was 62 years (range, 28-74), 45% were male and the median number of prior treatments was 2. Three dose limiting toxicities, all due to delayed count recovery past day 45, were observed in the escalation phase (n = 2/6 pts in the 10 mg/d day1-14 dose group and n = 1/6 in the in the 50 mg/d day1-10 dose group). The RP2D of Len in combination with MEC was 50 mg/d on days 1-10. Among the 14 pts treated at the RP2D, common grade 3/4 adverse events (AEs) regardless of causality were mainly hematologic including febrile neutropenia (36%). Overall 4 pts including none treated at the RP2D died during treatment. All of the on-treatment deaths, (grade 5 sepsis, n =1; infection, n=1; respiratory failure, n =2), were determined to be unrelated to the study drug. 32 pts were evaluable for response (one pt too early for assessment) with 12 pts achieving a CR and 1 pt a CRi with a total CR/CRi rate of 41% (95% CI: 24-59%). The median time to a neutrophil count of 1500/mL was 30 days and to a platelet count of 100,000/mL was 22 days. Conclusions: Len in combination with MEC re-induction chemotherapy for pts with relapsed or refractory AML was generally well tolerated and associated with an improved response rate as compared to historical controls. The safety profile was consistent with reported events in other MEC chemotherapy trials. Overall, these data suggest further exploration of high-dose Len in combination with MEC. Disclosures DeAngelo: Celgene: Consultancy; Agios: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Off Label Use: lenalidomide in AML. Fathi:Takeda Pharmaceuticals International Co.: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Exelexis: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Attar:Agios: Employment. Stone:Abbvie: Consultancy; Amgen: Consultancy; Agios: Consultancy; Celator: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Roche/Genetech: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Juno: Consultancy.

Dasatinib is a kinase inhibitor that inhibits BCR-ABL, Src family kinases, c-Kit, and platelet-derived growth factor receptor kinase. It is licensed for the first- and second-line treatment of chronic myeloid leukemia and second-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia on the basis of BCR-ABL inhibition, but the activity of dasatinib against additional molecular targets may enable treatment of other hematologic disorders. Potential targets for dasatinib in chronic lymphocytic leukemia (CLL) include Lyn (a Src family kinase), ABL, and the associated CD40 pathway. Although dasatinib monotherapy has modest clinical activity in CLL, ongoing studies are evaluating combination treatment. In acute myeloid leukemia (AML), FLT3, Lyn, c-Kit, and BCR-ABL are expressed in a subpopulation of patients. To date, clinical responses to dasatinib in patients with unselected AML have been mixed and larger studies are needed, particularly correlating clinical response to molecular markers. Imatinib has been used successfully to treat patients with chronic eosinophilic disorders with the FIP1L1-PDGFRA fusion kinase; limited clinical data indicate that dasatinib could be active in imatinib-resistant disease. Ongoing clinical studies should further define the value of dasatinib in these disorders.

Background Cellular immune deficiency is a consistent finding in patients with advanced head and neck cancer. Interleukin-2 and alpha-interferon are modulators of the immune system. Methods Eleven patients with recurrent head and neck cancer were treated in a Phase II study of recombinant human interleukin-2 (rIL-2) and alpha-2a-interferon (Roferon-A, Hoffmann-La Roche, Inc., Nutley, NJ). Each course consisted of rIL-2, 3 x 10(6) U/m2/day, as a continuous intravenous infusion over 24 hours for 4 days, and recombinant alpha-2a-interferon, 5 x 10(6) U/m2/day intramuscularly or subcutaneously daily for 4 days. This treatment was repeated weekly for 4 weeks, and then a second cycle was given after a 2-week break. Results Two patients (18%) achieved a partial response. Toxic effects were substantial. Three of 11 patients experienced Grade 3 hypotension, 3 patients had Grade 3 oliguria, and Grade 3 fatigue was one of the most common reasons for withdrawal from the study. There were no deaths or need for intensive care monitoring. Conclusions In view of the 18% response rate, additional investigation of biologic therapy in advanced head and neck cancer is warranted.

Tacrolimus (TRL) is an immunosuppressive drug characterized by a narrow therapeutic index, low bioavailability, and pharmacokinetic variability. Intravenous (IV) TRL may be needed whenever the oral route is unavailable. The small amount of infusion formulation (5 mg/mL) results in a large dilution and need for careful technical management of the infusion. This study addressed the feasibility to provide sublingual (SL) as an alternative to IV. TRL for transplanted patients. In a substudy, we performed a retrospective analysis of 17 lung and heart transplant patients using SL TRL. It included therapeutic drug monitoring and 4 area under curve (AUC) measurements. Patients received SL TRL on a dose-to-dose basis from the oral formulation. The mean age of the subjects (14 male, 3 female) was 35.3 ± 15.6 years; 146 trough (C 0 ) samples were collected during the SL period (15.8 ± 20.6 days) showing a conformity level of 90.4%. Mean dose, C 0 , and AUC of SL tacrolimus were 0.116 ± 0.096 mg/kg, 12.9 ± 5 ng/mL, and 230 ± 74 ng · h/mL, respectively, with an average 1 hour time to peak concentration. Acute rejection episodes, renal toxicity, and drug interactions were not observed. This study supported the convenience of short-term SL TRL administration, even in unconscious patients. Further investigations are needed to validate the dose range of the SL route.

Acute promyelocytic leukemia (APL) represents a subset of AML with t(15;17), responsiveness to ATRA, and a favorable prognosis, yet the impact of FLT3ITD mutations over wild-type (wt)FLT3 remains unclear. We retrospectively analyzed the outcome of 26 APL patients treated at our center according to their FLT3 receptor mutation status. We show that APL patients with an ITD mutation (n = 9) have a lower fibrinogen at presentation (103.5 vs. 235 mg/dl, p = 0.04) and a worse disease free survival (DFS) (p = 0.0114) but similar overall survival (OS) compared to patients with a wt FLT3 (n = 13). Our data suggests that APL with FLT3ITD represents a subset of APL patients who have a higher risk of relapse and should be treated with aggressive therapies upfront, possibly by including targeted therapy in the form of FLT3 inhibitors.

Characterization of gross chromosomal rearrangements, particularly translocations in neoplasms, has proven to be valuable in patient management by aiding in diagnosis, defining prognosis, and leading to new therapeutic interventions. In this report, we investigate two apparently balanced translocations, t(6;17)(q23.3;p13.3) and t(2;13)(p21;q14.11), in patients with myeloid neoplasms and uncover concomitant microdeletions associated with the breakpoints. Breakpoint mapping by fluorescence in situ hybridization (FISH) detected deletions at or adjacent to all breakpoints. Subsequently, array comparative genomic hybridization on the 244 K Agilent platform refined the deletion boundaries, revealing a 1.7 Mb deletion directly adjacent to the 6q23.3 breakpoint, and a 562 kb deletion at 17p13.3 in the first case. The second case was found to harbor a 195 kb deletion at 2p21 and a 1.4 Mb deletion distal to the 13q breakpoint at 13q14.3. Additionally, a 133 kb deletion within the breakpoint region at 13q14.11 and a 265 kb deletion proximal to the breakpoint were discovered, neither of which was detected by FISH. Although a gene fusion resulting from either novel rearrangement cannot be determined from these data, formation of a fusion transcript cannot be excluded because the resolution of the techniques used does not allow definite delineation of the breakpoint locations. Although the incidence and clinical relevance of these focal imbalances remains to be evaluated, the cases presented here support high resolution evaluation of presumably balanced rearrangements in neoplasms. Such imbalances may portend important hitherto unrecognized prognostic and diagnostic categories.

Oral ganciclovir (GCV) was replaced by prodrug valganciclovir (vGCV) for cytomegalovirus (CMV) prophylaxis. We assessed retrospectively (2005-2007) vGCV effectiveness and safety during prophylaxis and 4 months after, in heart (HTx) and lung transplantation (LTx), including lung transplant for cystic fibrosis (CFTx). Patients with stable renal function received vGCV 900 mg daily during 3-6 and 8-12 months in HTx and LTx. Effectiveness was assessed by antigenemia (pp65Ag) and a GCV therapeutic drug monitoring to document exposure. A total of 32 patients (11 HTx, 7 LTx, and 14 CFTx) received vGCV for 106+/-67 days in HTx versus 270+/-85 days in LTx and CFTx. Doses were 700+/-225, 915+/-60, and 820+/-150 mg/24 h in HTx, LTx, and CFTx showing acceptable mean trough GCV 0.75+/-0.5 mg/L. Two of 9 cases of neutropenia were attributable to vGCV. Three CMV donor-positive/recipient-negative CFTx patients presented positive pp65Ag; 2 developed CMV disease (6%). We found that vGCV 900 mg, adapted to renal function, was effective and safe for long CMV prophylaxis together with efficient exposure in thoracic transplantation.