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  • 1
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1597-1597
    Abstract: Introduction: Activating mutations in FLT3 are present in a significant fraction of acute myeloid leukemia (AML) cases. Patients with FLT3 mutations have a significantly worse prognosis than patients with wild type FLT3, suggesting that the activated kinase is a driver of the disease. AC220 is a novel class III receptor tyrosine kinase (RTK) inhibitor. It has highly potent activity against FLT3 and is highly selective for wild type and mutant FLT3 and other class III RTKs, including KIT, CSF1R/FMS, RET and PDGFR. AC220 is currently in a phase I clinical study for relapsed or refractory AML patients. Human pharmacokinetic (PK) data from early cohorts are presented along with the preclinical profile in support of the rationale for the clinical evaluation of AC220 in AML. Methods: Cellular efficacy of AC220 was evaluated in the FLT3-dependent human leukemia cell line MV4;11. This cell line was implanted in a mouse xenograft model, which was used to assess animal efficacy. In preclinical studies, pharmacokinetics were determined in rats and dogs. The clinical study is a phase I, first-in-man, multi-center, open label, sequential dose escalation study. AC220 is administered once daily as an oral solution for 14 days with a starting dose of 12 mg. At least three centers in the U.S. enrolled AML patients into three-patient cohorts. Results: AC220 inhibits proliferation of MV4;11 cells with subnanomolar potency (IC50 = 0.3 nM). In the mouse MV4;11 xenograft model, tumor regression is observed at 3 mg/kg (9 mg/m2, p.o., qd), and tumor growth inhibition at 1 mg/kg (3 mg/m2, p.o., qd). The terminal half-life is 5.7 hours in rats and 5.9 hours in dogs. In the clinical study, one male and two female patients were enrolled into cohort 1. The weight range for these patients is 77.9 to 101.27 kg. The average plasma concentrations at the 12 mg dose are 11.2 ng/mL at day 1, 37.9 ng/mL at day 8 and 42.9 ng/mL (0.06 μM) at steady state (by day 15), with an apparent terminal half-life of at least 2.8 days. Inter-patient variability of steady state plasma concentrations within the 3-patient cohort is low. Conclusions: At the human dose of 12 mg, AC220 is well tolerated and absorbed. It has a long terminal half-life and the inter-patient pharmacokinetic variability is low. Steady state is predicted to be reached within 8 to 14 days with minor peaks and troughs. There is a strong correlation between efficacy in the mouse model and AC220 plasma levels (adjusted for plasma protein binding) relative to potency in the MV4;11 cell-based assay. At the human dose of 12 mg (average 5.2 mg/m2), the plasma level of AC220 at steady state (0.06 μM, when adjusted for plasma protein binding) is approximately twofold higher than the MV4;11 cell IC50. Continued exploration in patients is warranted to determine the role of AC220 in the treatment of AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 2
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 767-767
    Abstract: Activating mutations in the receptor tyrosine kinase FLT3 are present in approximately 30% of patients (pts) with acute myeloid leukemia (AML), and they have a significantly worse prognosis than pts with wild type (WT) FLT3, suggesting that the activated kinase is a driver of the disease and a potential target for kinase inhibitor therapy. AC220 is a novel 2nd generation class III receptor tyrosine kinase (RTK) inhibitor with potent in vitro and in vivo activity in FLT3-dependent tumors. It is highly selective for WT and mutant FLT3 and several other class III RTKs, including KIT, CSF1R, RET and PDGFR. AC220 is in a first-in-human phase 1 study for relapsed or refractory AML pts, unselected for FLT3 mutations. The study has a standard 3+3 dose escalation design with 50% dose increments. AC220 is administered once daily as an oral solution for 14 days followed by a 14 day rest period (1 cycle) with a starting dose of 12 mg. Concurrently, pts are being dosed on a continuous dosing regimen starting at 200 mg/day for 28 days (1 cycle). Pts with clinical benefit may continue to receive further cycles. Currently, 52 pts have been dosed with AC220 up to 450 mg/day (10 dose cohorts). Median age was 60 yrs (range, 23 to 86 yrs), median number of prior therapies was 3 (range, 0 to 8) and 2 pts had prior allogeneic hematopoietic stem cell transplant (HSCT). Two elderly patients (age ≥ 78 yrs) unfit for induction chemotherapy were previously untreated. Fifteen patients have FLT3 mutations (12 ITD and 3 TKD), 25 are WT, and 12 are undetermined. Pts are also evaluated for PK, pFLT3, pSTAT5, FLT3 genotyping and ex vivo plasma inhibitory activity. AC220 is well tolerated and MTD has not yet been observed with either schedule. One pt had a possibly drug-related DLT in the 18 mg cohort (grade 3 CHF, although pt had a pre-existing heart condition) leading to cohort expansion, but no other cases of drug-related CHF or other DLT have been seen. Other possibly drug-related AEs (most frequently gastrointestinal events) were mild (grade ≤ 2). Response data based on investigator’s assessment are available on the first 45 pts. Responses were observed in 11 (24%) pts. Four pts achieved a complete response (CR) – 2 with incomplete platelet recovery (CRp) and 2 with incomplete platelet and neutrophil recovery (CRi), one of these pts also had complete resolution of leukemia cutis. In addition, 7 pts had partial responses (PR, defined as a decrease of ≥ 50% blasts to levels of 5%–25% in the bone marrow). Most responses (8/11, 73%) occurred after cycle 1 and one was observed after cycle 3. Median duration of response is 18 weeks (range, 4 to 26+ weeks). Three responders are FLT3 mutants (2 ITD and 1TKD), 5 are WT, 3 are undetermined. Six of the 9 non-responding pts with ITD mutations had initial rapid clearing of peripheral blasts with intermittent AC220 dosing, but subsequently progressed or had disease-related mortality. All these pts had aggressive disease and received a median of 6 prior treatment regimens (range, 3 to 8). AC220 plasma exposure is sustained between dose intervals and continues to increase in a dose-proportional manner from 12 mg to 300 mg. FLT3 phosphorylation is strongly suppressed when plasma obtained from study pts is tested ex vivo in FLT3-ITD and WT cell lines at 12 mg and 60 mg doses, respectively. Assessments of pFLT3 and pSTAT5 from treated pts’ peripheral blood are ongoing and will be presented. Encouraging preliminary efficacy results and an acceptable safety profile warrants continued evaluation of AC220 as a single agent and in combination with other therapeutics for the treatment of AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 3
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2076-2076
    Abstract: Abstract 2076 Poster Board II-53 Background Recently, further refinement of the “unfavorable” cytogenetic category in AML demonstrated that a “monosomal karyotype” (MK+) – defined as two or more distinct autosomal chromosome monosomies or one single autosomal monosomy in the presence of structural abnormalities – carries a markedly inferior prognosis to that of a “non-monosomal karyotype” (MK-) – defined as a group with various non-core binding factor (CBF) cytogenetic abnormalities but who are MK negative (J. Clin Onc 26:4791). This finding was based on data from patients predominantly with de novo AML. We analysed data from a phase II trial of patients with sAML to examine whether the monosomal karyotype is also predictive of poor outcome in sAML patients. Methods The karyotypes of pre-treatment blast cells from previously untreated sAML patients on a phase II study were reviewed to identify categories of core binding factor karyotype (CBF), normal karyotype (CN), MK+ and MK- (as defined above), and compared to clinical outcomes. Patients on the study all received induction therapy with amonafide 600 mg/m2/day IV days 1-5 and cytarabine 200 mg/m2/day IV days 1-7. Consolidation consisted of stem cell transplant (HSCT, n=10) or intermediate-dose (IDAC, n=13)/high-dose (HiDAC, n=7) cytarabine, depending on age and available HSCT donors. Results 88 patients were treated. 2/88 (2%) were CBF, 29/88 (33%) were CN, 16/88 (18%) were MK+ and 31/88 (35%) were MK-. Patients with CBF and the 10 patients with unknown karyotype at baseline were excluded from the analysis. CR+CRi rate by karyotypic group was 19/29 (66%) for CN, 11/31 (35%) for MK-, 2/16 (13%) for MK+ (CN vs MK- p & lt;0.05; CN vs MK+ p & lt;0.05; MK- vs MK+ p=0.09). Median duration of remission was 282 days for CN, 304 days for MK-, and not reached for the 2 MK+ patients who achieved CR (p=NS). Median overall survival: 304 days CN, 145 days MK- and 144 days MK+ (Log rank test for survival: CN vs MK- p=0.07; CN vs MK+ p & lt;0.05; MK- vs MK+ p=0.06). Conclusions In this study of 88 patients with secondary AML, a monosomal karyotype was predictive of inferior response to therapy compared with both a normal karyotype and a non-monosomal “unfavorable” karyotype. Importantly, the 2-year overall survival in the MK+ group was significantly inferior to that in the CN group. Of note durable complete remissions were observed in responders regardless of karyotype. Though the number of patients in this study is relatively small, to our knowledge this is the only prospectively defined study of sAML patients demonstrating a significantly adverse impact of monosomal karyotype as compared with other “unfavorable” karyotypes. Further data to address the prognostic and predictive significance of specific cytogenetic abnormalities in sAML will be obtained from a currently enrolling 450-patient phase III randomized trial of amonafide + cytarabine vs daunorubicin + cytarabine in patients with sAML (ACCEDE). Disclosures: Downie: Antisoma: Research Funding. Erba:Lilly: Research Funding; Antisoma: Research Funding; Wyeth: Research Funding; Cephalon: Honoraria, Research Funding; MGI Pharma: Honoraria; Pharmion: Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. Stone:Celgene: Consultancy, Speakers Bureau; Merck: Consultancy; Genzyme: Consultancy; Eisai: Consultancy. Rizzieri:Antisoma: Research Funding. Foran:Antisoma: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1954-1954
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1954-1954
    Abstract: Abstract 1954 Poster Board I-977 Introduction: Despite advances in treatment and a well-characterized prognostic index, significant heterogeneity remains in DLBCL survival. Preliminary data suggest a potential survival disparity based on race/ethnicity or socioeconomic status (SES). To evaluate the impact of these and other variables on survival we performed an analysis in the ethnically diverse population-based California Cancer Registry (CCR). We utilized Neighborhood SES, an index of 7 census measures of education, income, occupation & cost of living, based on the residential census-block group at diagnosis. Each census-block group comprises ∼1500 residents. Neighborhood SES has been shown to be significantly associated with survival after Follicular Lymphoma (JCO 27:3044, 2009). Methods: All pts with DLBCL (ICD-O-3 codes 9680 & 9684) diagnosed from Jan 1988 to Dec 2007 and reported to CCR were included in the analysis, including n=16,892 diagnosed from 1988-2000, and n=11,916 from 2001-2007 (total study pop'n =28,808). HIV/AIDS pts were excluded, as were n=63 with Mediastinal LBCL & n=10 with primary effusion lymphoma. The mean age was 63 yrs, and the cohort was 53% male. Between time periods, there was a relative increase in Hispanic pts [15.4% (1988-2000) to 20.8% (2001-2007), p 〈 0.001], and a 4% increase in advanced stage from 42% (1988-2000) to 46% (2001-2007) (p 〈 0.001). Neighborhood SES was stratified into quintiles from lowest (SES-1) to highest (SES-5), the pt distribution was: SES-1, 14%; SES-2, 18%; SES-3, 21%; SES-4, 23%; and SES-5, 24%. To evaluate the impact of prognostic factors (particularly diagnosis period, SES, and race/ethnicity) on overall survival (OS) & disease-specific survival (DSS) we used Cox proportional hazards regression to calculate hazard ratios (HR) for death with 95% CI's. Multivariate regression models included variables significant at p 〈 0.15 in univariate models or with a priori hypotheses for inclusion. Results are presented by stage at diagnosis [Localized/Regional (LocReg) vs. Advanced (ADV)]. Results: There was a significant improvement in OS in patients diagnosed after 2001 for both LocReg (HR 0.87, 95%CI 0.82-0.91, p 〈 0.001) and ADV stage (HR 0.69, 95%CI 0.66-0.72, p 〈 0.001), which correlates with the introduction of rituximab into therapy for DLBCL. As expected, age 〉 60 years was associated with a significantly worse OS for LocReg (HR 3.06, 95%CI 2.90-3.24) and ADV stage (2.02, 95%CI 1.93-2.12). Females also had significantly better OS compared with males (Loc-Reg - HR 0.90, 95%CI 0.86-0.94; ADV - HR 0.89, 95%CI 0.85-0.93). There was no significant impact of race/ethnicity on survival with the exception of non-Hispanic Asian/Pacific Islanders (NH A/PI) with ADV stage, for whom OS was significantly inferior compared with whites (HR 1.18, 95%CI 1.09-1.27, p 〈 0.001). Compared with the highest quintile (SES-5), there was a significant effect of lower neighborhood SES on OS and DSS (see Table). Conclusion: There has been a significant improvement in survival after DLBCL since 2001, but patients in the lowest SES-1 quintile have a 34% higher risk of death from any cause and 20% higher risk for death from lymphoma than those in the highest SES-5. In this model, race/ethnicity did not have a significant impact on survival with the exception of NH A/PI with ADV stage. Studies to understand and address these socioeconomic disparities are urgently required in order to extend the improvements in DLBCL survival more effectively. Disclosures: Foran: Genentech: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 5
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4635-4635
    Abstract: Despite significant advances in the treatment of acute myeloid leukemia (AML) in younger adults, there has been little progress in the treatment of older patients (age≥60 years), who comprise the majority of those with the disease. Clofarabine is a purine nucleoside analog with single agent activity in patients with relapsed AML. In addition, clofarabine potentiates Ara-C cytotoxicity in vitro through increased intracellular Ara-CTP accumulation, making this an attractive combination. A phase I/II study has therefore been initiated combining clofarabine with standard dose cytarabine (100mg/m2/day x 7) in pts age ≥60 years with de novo AML. The starting dose of clofarabine was 30mg/m2/day x 5 beginning on day 2 (Dose level I). Patients were accrued in cohorts of 3–6 to establish dose limiting toxicity (DLT); cohort expansion at the maximum tolerated dose (MTD) is planned in phase II using a Simon 2-stage design. Detailed plasma and intracellular pharmacokinetics were performed during induction therapy with Ara-C alone (day 1), and following the addition of clofarabine (day 2) to determine the effect of clofarabine on intracellular Ara-CTP accumulation. Pts with residual AML on d14–21 restaging bone marrow (BM) biopsy were eligible to receive Re-Induction with 5 days of clofarabine & Ara-C. Those achieving complete remission were also eligible to receive 1–2 cycles of consolidation with Ara-C (d1–5) & clofarabine (total 3 cycles of planned therapy). Dose limiting toxicity was encountered at dose level I (see Table 1). 2/4 pts achieved CR, in 1 case with residual cytogenetic abnormality, and there were 2 treatment-related deaths from infxn (culture neg sepsis, n=1; Candida tropicalis, n=1). In the latter case (pt 4), BM aplasia was achieved, but the pt died on d25 prior to hematologic recovery. In view of the DLT, the protocol has therefore been amended to allow 25% dose de-escalation of clofarabine to Dose Level -I (22.5mg/m2/day x 5), and to limit eligibilty to pts age 60–75 yrs inclusive. Routine use of aggressive pre-hydration and antibiotic and antifungal prophylaxis is now mandated. Clofarabine & cytarabine is a highly active induction regimen in older adults age ≥60 yrs with de novo AML, but has significant myelosuppressive and infectious toxicity. The study is proceeding in phase I at Dose Level -I to establish the MTD. Phase I, Dose Level I PT AGE, GENDER FAB CYTOGENETICS F/U BM TOXICITY (Gr.III/IV) OUTCOME MLD - multilineage dysplasia; F & N - fever & neutropenia; CR - complete remission 1 66M M2 Diploid D21: residual AML renal, infxn Death 2 61M M2 Complex D14: aplastic F & N CR 3 69M M2 with MLD Intermediate Risk D21: recovering F & N CR 4 77F M2 Diploid D14: aplastic renal, infxn, capillary leak Death
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 6
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3578-3578
    Abstract: Background: Despite a lower incidence of non-Hodgkin’s lymphoma (NHL) and specifically diffuse large B-cell lymphoma (DLBCL), the most common histologic subtype, previous studies suggest that blacks have a higher disease-specific mortality from NHL than whites. To study this disparity, we looked at the impact of race, treatment delays and the use of rituximab on survival in NHL and DLBCL. To control for access to care, we focused on a population of patients with Medicare benefits. Methods: After establishing a SEER-Medicare Data-Use Agreement and obtaining IRB approval, we used the linked SEER-Medicare database for NHL patients diagnosed from 1995 through 2002, with claims data through 2003. Multivariable logistic regressions were used to assess the difference between race and rates of survival, NHL histology, and the likelihood of receiving treatment within 90 days and of receiving rituximab at any time during the course of NHL treatment. Results: Among 41,704 NHL cases, 35,014 (85%) cases were in whites and 2,287 (5.5%) were in blacks. Of the 14,831 total cases of DLBCL, 12,449 (84%) were in whites and 715 (4.8%) were in blacks. Despite a lower incidence of NHL, blacks had a lower 1-year survival for NHL compared to whites (OR 0.68 [95% CI 0.61–0.76]). Blacks also had a lower 1-year survival for DLBCL compared to whites (OR 0.63[95% CI 0.53–0.75] ). Patients treated within 90 days of diagnosis had improved 1-year survival for NHL (OR 1.10 [95% CI 1.03–1.18]) and for DLBCL (OR 1.60 [95% CI 1.47–1.75] ). When controlling for age, gender and income, blacks were less likely than whites to be treated within 90 days of a NHL diagnosis (OR 0.599 [95% CI 0.526–0.681]). The use of rituximab was associated with improved 1-year survival for NHL (OR 3.67 [95% CI 3.37–4.00] ) and specifically for DLBCL (OR 3.01 [95% CI 2.66–3.40]). However, blacks were significantly less likely to receive rituximab for NHL (OR 0.55 [95% CI [0.47–0.63] ) and specifically for DLBCL (OR 0.71[95% CI 0.57–0.90]). An analysis of two and three year survival for NHL and DLBCL yielded similar results for the impact of race, treatment delays and use of rituximab. Conclusions: Blacks are diagnosed with NHL and specifically DLBCL less frequently than whites but have significantly lower 1-year survival rates. Blacks were significantly less likely to begin treatment within 90 days of a NHL diagnosis. In addition, blacks were significantly less likely to receive rituximab despite presumed equal access to healthcare with Medicare benefits. The reason for this racial disparity is unclear. Studies to further characterize the disparity are needed.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 7
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3580-3580
    Abstract: Background: Despite the existence of well-established clinical prognostic indices for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the 2 most common subtypes of NHL, significant heterogeneity in survival remains even within prognostic groups. SES has not previously been evaluated as a prognostic factor for NHL, particularly using an unselected patient population. We therefore used the large multiethnic CCR to examine NHL survival according to histology, race/ethnicity and neighborhood SES. Methods: NHL pts were identified from the CCR for the period 1988–97 using standardized ICD-0-3 classifications (morphology codes 9690–99 for FL & 9680–84 for DLBCL). Patients with evidence of HIV/AIDS were excluded. Neighborhood SES was assigned based on the address of residence at diagnosis, according to 1990 US Census Bureau census block group (each block contains about 1500 residents), and is based upon principal components of 7 indicator variables of SES (education level, proportion with blue collar job, proportion unemployed, median household income, proportion below 200% of poverty line, median rent & median home value). Using this index, we assigned each patient into an SES quintile (SES-1 lowest, SES-5 highest) based on the statewide distribution of neighborhood SES. We computed 5-year relative survival ± standard error (SE) with SEER*Stat software using customized race and SES-specific life tables based on US Census Bureau estimates for California residents. Results: Unselected DLBCL pts [n=13,604; comprising 73% non-Hispanic White (W), 4% Black (B), 14% Hispanic (H), 8% Asian/Pacific Islander (A)] & FL pts (n=7372; 82% W, 3% B, 11% H, 4% A) were identified. The overall 5 yr relative survival for DLBCL was 45.5% (SE 0.5) and for FL was 71.1% (SE 0.6); females had a better survival than males for DLBCL [F 48.3% (SE 0.7) vs. M 42.3% (SE 0.6)] but not for FL. Lower SES was associated with inferior survival for both DLBCL & FL (Table 1). Within SES groups there were not significant racial/ethnic differences in survival. However, in DLBCL, B (34%) and H (33%) pts were proportionally more likely to be in SES-1 than W (9%) or A pts (15%), and less likely to be in SES-5 (9% B, 10% H) than W (27%) or A (22%) pts. Similarly, in FL, B (39%) & H (26%) pts were also more likely than W (8%) & A (10%) pts to be in SES-1 and less likely to be in SES-5 (W-29%, A-32%, B-10%, H-11%). Conclusion: SES predicts survival in DLBCL and FL. Race/ethnicity differences in SES distribution are apparent in NHL patients, but when stratified by SES, race/ethnicity does not appear to predict for significant differences in NHL survival. 5 Year Relative Survival in DLBCL & FL by SES & Race SES-1 (%) SE (%) n SES-5 (%) SE (%) n W-non-Hispanic White; A-Asian/Pacific Islander; B-Black; H-Hispanic DLBCL 40.6 1.3 1905 49.4 1.0 3192 W 38.4 1.9 915 49.4 1.1 2701 A 44.0 4.2 168 48.2 3.5 244 B 45.0 4.2 185 54.3 7.3 51 H 41.6 2.1 637 48.9 4.0 196 FL 66.4 2.1 823 76.6 1.2 1959 W 66.3 2.7 502 77.1 1.2 1753 A 65.4 10.0 30 72.0 5.0 93 B 69.1 6.5 85 76.1 10.0 22 H 65.9 3.8 206 71.8 5.4 91
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 8
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2009
    In:  Journal of Clinical Oncology Vol. 27, No. 18 ( 2009-06-20), p. 3044-3051
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 27, No. 18 ( 2009-06-20), p. 3044-3051
    Abstract: A recent report suggested improvements in survival after follicular lymphoma (FL), but not for all racial/ethnic groups. To better understand the reasons for these FL survival differences, we examined the joint influences of diagnostic period, race/ethnicity, and neighborhood socioeconomic status (SES) on survival in a large population-based case series. Methods All patients (n = 15,937) diagnosed with FL between 1988 and 2005 in California were observed for vital status through November 2007. Overall and FL-specific survival were analyzed with Kaplan-Meier and Cox proportional hazards regression. Neighborhood SES was assigned from United States Census data using residence at diagnosis. Results Overall and FL-specific survival improved 22% and 37%, respectively, from 1988 to 1997 to 1998 to 2005, and were observed in all racial/ethnic groups. Asian/Pacific Islanders had better survival than non-Hispanic white, Hispanic, and black patients who had similar outcomes. Lower neighborhood SES was associated with worse survival in patients across all stages of disease (P for trend 〈 .01). Patients with the lowest SES quintile had a 49% increased risk of death from all causes (hazard ratio [HR] = 1.49, 95% CI, 1.30 to 1.72) and 31% increased risk of death from FL (HR = 1.31; 95% CI, 1.06 to 1.60) than patients with the highest SES. Conclusion Evolving therapies have likely led to improvements in survival after FL. Although improvements have occurred within all racial/ethnic groups, lower neighborhood SES was significantly associated with substantially poorer survival.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2009
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  • 9
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 636-636
    Abstract: Abstract 636 Activating mutations in the FLT3 RTK are present in ∼30% of AML patients (pts), who have a significantly worse prognosis than pts with wild type (WT) FLT3. AC220 is a novel 2nd generation RTK inhibitor with potent in vitro and in vivo activity in FLT3- and KIT-dependent tumor cell lines. It is highly selective for both WT and mutant FLT3 with significant activity against KIT. A first-in-human Phase 1 study investigating AC220 in predominantly relapsed or refractory AML pts, unselected for FLT3 mutations, was recently completed, using a standard 3+3 dose escalation with 50% dose increments. AC220 was administered once daily as an oral solution initially with an intermittent dosing (ID) regimen: 14 days on and 14 days off (1 cycle). Starting dose was escalated from 12 to 450 mg/day ID. Additional cohorts were investigated on a continuous dosing (CD) regimen: 200 and 300 mg/day for 28 days (1 cycle). A total of 76 pts (46 male, 30 female) were dosed with AC220. Median age was 60 yrs (23-86), median number of prior therapies was 4 (0-9), 12 pts had prior allogeneic transplant and 3 elderly pts (≥72 yrs) unfit for induction chemotherapy were previously untreated. Eighteen pts (24%) had FLT3 ITD mutations, 47 (62%) were WT, and 11 (14%) were undetermined. Pts were also evaluated for PK, phosphorylated (p) FLT3, pKIT, pSTAT5, and ex vivo plasma inhibitory activity. AC220 plasma exposure was sustained between dose intervals and continued to increase in a dose-proportional manner from 12 to 450 mg with a half-life of ∼1.5 days. An active metabolite, AC886, was detected that has similar potency and activity to AC220. Patient plasma at '12 mg potently inhibited pFLT3 in ex vivo FLT3-ITD cell lines and complete inhibition of pFLT3 in WT cell lines was observed at higher doses. Target inhibition was also observed, with suppression of pFLT3, pSTAT5 and pKIT in peripheral blasts. The most commonly reported possibly drug-related AEs were GI events, peripheral edema, and dysguesia, which were Grade ≤2. DLT was observed at 300 mg CD and 200 mg CD was declared as the MTD. Two pts at 300 mg CD had possibly study drug-related DLTs with grade 3 QTc prolongation, but had confounding factors including concomitant medications known to prolong QTc. Responses (IWG criteria) were observed in 23 (30%) pts. PR and CR were observed as low as the 18 and 40 mg cohorts, respectively. Most responses occurred within cycle 1. Overall, 9 (12%) pts had a complete response (CR) with 2 CR, 5 CRi, and 2 CRp. One of these pts also had complete resolution of leukemia cutis. In addition, 14 (18%) pts achieved PR. Overall median duration of response (MDOR) was 14 (4-62+) weeks and overall median survival (MS) was 14 (1-68+) weeks. In FLT3-ITD pts the MDOR was 12 (4-27+) weeks and the MS was 18 (3-42) weeks. In FLT3-WT pts the MDOR was 32 (8-62+) weeks and the MS was 11 (1-68+) weeks. 10 (56%) of 18 FLT3-ITD pts were responders (1 CR, 3 CRi, 6 PR), 9 (19%) of 47 FLT3-WT pts (1 CRi, 2 CRp, 6 PR), and 4 (36%) of 11 undetermined pts (1 CR, 1 CRi, 2 PR). At 200 mg CD (MTD expansion), 4 of 6 FLT3-ITD pts responded (1 CR, 1 CRp, 1 CRi, 1 PR). Of the 4 responders, 2 failed prior treatment with sorafenib and 2 previously refractory pts went onto transplant. The 2 FLT3-ITD non-responders had 6 and 8 prior lines of therapy, respectively. These encouraging efficacy results and an acceptable safety profile warrant continued evaluation of AC220 as monotherapy and in combination therapy for the treatment of AML. Phase 2 studies in FLT3-ITD positive and WT pts are in progress. Disclosures: Cortes: Ambit Biosciences: Research Funding. Foran:Ambit Biosciences: Research Funding. Ghirdaladze:Ambit Biosciences: Research Funding. DeVetten:Ambit Biosciences: Research Funding. Zodelava:Ambit Biosciences: Research Funding. Holman:Ambit Biosciences: Research Funding. Levis:Ambit Biosciences: Consultancy, Research Funding. James:Ambit Biosciences: Employment. Zarringkar:Ambit Biosciences: Employment. Gunawardane:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment. Padre:Ambit Biosciences: Employment. Wierenga:Ambit Biosciences: Employment. Corringham:Ambit Biosciences: Employment. Trikha:Ambit Biosciences: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 10
    In: The American Journal of Cardiology, Elsevier BV, Vol. 95, No. 8 ( 2005-04), p. 948-954
    Type of Medium: Online Resource
    ISSN: 0002-9149
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2005
    detail.hit.zdb_id: 2019595-3
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