Tolerability and hematologic improvement assessed using three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7083-7083 ◽  
Author(s):  
R. M. Lyons ◽  
T. Cosgriff ◽  
S. Modi ◽  
H. McIntyre ◽  
C. L. Beach ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Working Group ◽  
Open Label ◽  
Dosing Schedule ◽  
Fab Classification ◽  
Open Label Trial ◽  
Grade 3 ◽  
Treatment Related Mortality ◽  
Related Mortality

7083 Background: At a dosing schedule of 75 mg/m2/day SC for 7 days every 4 weeks, azacitidine is an effective and safe treatment (Tx) for patients (pts) with myelodysplastic syndromes (MDS) (JCO 2002; 20:2429). An alternative dosing schedule that eliminates the need for weekend dosing would be more convenient to pts and clinicians. Methods: In this phase II, multicenter, open-label trial, pts with MDS were randomized to 1 of 3 regimens that were repeated every 4 weeks: AZA 5–2-2 (75 mg/m2/day × 5 days, followed by 2 days no Tx, followed by 75 mg/m2/day × 2 days), AZA 5–2-5 (50 mg/m2/day × 5 days, followed by 2 days no Tx, followed by 50 mg/m2/day × 5 days) or AZA 5 (75 mg/m2/day × 5 days). To determine if response/improvement according to International Working Group criteria (Blood 2000; 96:3671) can be maintained after 6 cycles, the study was amended to include a 12-month maintenance comparing AZA 5 every 4 weeks with AZA 5 every 6 weeks. Results: As of Nov. 30, 2006, 138 pts have been randomized to AZA 5–2-2 (n=46), AZA 5–2-5 (n=47) and AZA 5 (n=45). Most pts are RA (43%) or RAEB (30%), based on FAB classification. Of 104 pts who have received =2 cycles of Tx, hematologic improvement (major or minor in at least 1 cell line) occurred in 63% (65) of the patients ( Table ). Of these pts, 14% had a bi-lineage (AZA 5–2-2: 11%, AZA 5–2-5: 10%, AZA 5: 22%) and 6% had a tri-lineage AZA 5–2-2: 6%, AZA 5–2-5: 7%, AZA 5: 5%) response (based on any improvement). Ongoing pts in the study include AZA 5–2-2: 41% (19/46), AZA 5–2-5: 47% (22/47), and AZA 5: 58% (26/45). No treatment-related mortality has been reported. Most Tx-related grade 3 or 4 events were hematological (AZA 5–2-2: 39%, AZA 5–2-5: 24%, AZA 5: 16%). Updated data, including several pts who have completed at least 6 cycles maintenance, will be available at the time of the meeting. Conclusions: These data indicate that the 3 alternative azacitidine dosing schedules are safe, effective, and similar in efficacy with the FDA-approved regimen. [Table: see text] [Table: see text]

Hematologic Improvement, Transfusion Independence, and Safety Assessed Using Three Alternative Dosing Schedules of Azacitidine in Patients with Myelodysplastic Syndromes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2662-2662 ◽  
Author(s):  
Roger M. Lyons ◽  
Thomas Cosgriff ◽  
Sanjiv Modi ◽  
Heidi McIntyre ◽  
C.L. Beach ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Study ◽  
Transfusion Independence ◽  
Fab Classification ◽  
Common Grade ◽  
Grade 3 ◽  
To Receive

Abstract Efficacy and safety of azacitidine (Vidaza®), at the FDA-approved dosing schedule of 75 mg/m2/day x 7 days every 28 days, was demonstrated in a phase III CALGB study by Silverman et al (JCO2002; 20:2429) for the treatment of myelodysplastic syndromes (MDS). The objective of this phase II, multicenter, randomized, open-label study in all FAB subtypes of MDS was to study the treatment response and safety of 3 alternative subcutaneous azacitidine dosing schedules, eliminating the need for weekend azacitidine injections. Patients were randomized to either AZA 5-2-2 (75 mg/m2 day x 5 days, followed by 2 days no treatment, followed by 75 mg/m2/day x 2 days), AZA 5-2-5 (50 mg/m2/day x 5 days, followed by 2 days no treatment, followed by 50 mg/m2/day x 5 days) or AZA 5 (75 mg/m2/day x 5 days). After 6 cycles of azacitidine, patients meeting International Working Group MDS response/improvement criteria (Blood2000; 96:3671), defined as complete remission, partial remission, stable disease, or hematologic improvement, were eligible to receive an additional 12 cycles. As of July 1st, a total of 106 patients have been randomized in the AZA 5-2-2 (n=33), AZA 5-2-5 (n=35), and AZA 5 (n=38) treatment arms. Based on FAB classification, most patients have RA (42%, 45/106) or RAEB (30%, 32/106). Of 80 patients who have received ≥2 cycles of treatment, hematologic improvement (major or minor in at least 1 cell line) occurred in 58% (46/80) of the patients (Table). Median time to improvement in the 3 arms ranged between 1 and 3 cycles (AZA 5-2-2: 1.1, AZA 5-2-5: 3.0, AZA 5: 2.6). Of 38 patients who were RBC transfusion dependent at baseline, 27 (71%) became independent (AZA 5-2-2: 59%, 10/17, AZA 5-2-5: 89%, 8/9; AZA 5: 75%, 9/12). The most common grade 3 or 4 events included neutropenia 29%, 28/98 (AZA 5-2-2: 44%, 14/32; AZA 5-2-5: 20%, 6/30, and AZA 5: 22%, 8/36), thrombocytopenia 15%, 15/98 (AZA 5-2-2: 28%, 9/32; AZA 5-2-5: 10%, 3/30, and AZA 5: 8%, 3/36) and anemia 12%, 12/98 (AZA 5-2-2: 16%, 5/32; AZA 5-2-5: 17%, 5/30, and AZA 5: 6%, 2/36). The frequency of patients with a grade 3 or 4 infection was 15%, 15/98 (AZA 5-2-2: 19%, 6/32; AZA 5-2-5: 23%, 7/30; AZA 5: 6%, 2/36) or hemorrhage was 4%, 4/98 (AZA 5-2-2: 6%, 2/32; AZA 5-2-5: 7%, 2/30; AZA 5: 0/36). Updated data will be available at the time of the meeting. Based on preliminary results, these data indicate that the 3 alternative dosing schedules provide clinical benefit (i.e., transfusion independence and hematologic improvement) and are consistent with the FDA-approved 75 mg/m2/day x 7 days dosing results from previous CALGB studies. Table: Hematologic Improvement Response Rates

scholarly journals Combination of Decitabine and ATRA in Newly Diagnosed Myelodysplastic Syndromes Subtype EB-Interim Analysis of a Multicenter, Randomized, Open-Label Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 539-539
Author(s):  
Xinping Zhou ◽  
Fanjun Meng ◽  
Yanjuan Lin ◽  
Zheng Ge ◽  
Yuemin Kuang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Myelodysplastic Syndromes ◽  
Interim Analysis ◽  
Overall Response Rate ◽  
Response Rate ◽  
Newly Diagnosed ◽  
Open Label ◽  
Open Label Trial ◽  
Grade 3

Abstract Background: HMAs are mainstay treatment of higher-risk myelodysplastic syndromes (MDS). However, clinical outcomes of patients treated with decitabine (DEC) monotherapy were far from satisfactory with an overall response rate (ORR) of 33%-55.4% and an overall survival (OS) of 17.7-22 months. Some clinical researches reported that the addition of all-trans retinoic acid (ATRA) to DEC increased response rate and prolonged survival of MDS and elderly acute myeloid leukemia (AML) patients. Our data showed ATRA enhanced the cytotoxic effect of DEC on MDS via activating RARα-Nrf2 complex (2021 EHA abstract EP891). These findings suggested that addition of ATRA to DEC in treatment-naive patients may improve response rate based on the synergetic function. We therefore conducted a study of combination of DEC and ATRA in MDS subtype excessive blasts (EB) patients. Methods: In this randomized, multicenter, open-label trial, patients with newly diagnosed MDS subtype EB based on the 2016 WHO classification from 7 different tertiary medical centers in China were included. Patients were randomized 1:1 to receive either oral ATRA (25mg/m 2/day on days 1-28) plus DEC (20 mg/m 2 daily on days 1-5) or DEC monotherapy（Figure 1）. The primary endpoint was overall response rate ORR, defined as complete remission (CR), partial remission (PR), marrow complete remission (mCR), or hematological improvement (HI). Key secondary endpoints were mCR, HI, overall survival (OS), and progress free survival (PFS). Response was assessed after completion of four cycles of treatment. For patients who bridged to allo-HSCT later on and did not complete four cycles of treatments, response was defined as best response ever observed before receiving allo-HSCT. Here, we report results of the interim analysis. Results: Between May 2018 and July 2021, 165 patients were randomly allocated into either DEC plus ATRA (n=82) or DEC monotherapy (n=83). 63.6% of patients were male and 36.4% were female, with a median age of 62 years (range, 19 to 81 years). 38.8% of patients had EB1 and 61.2% had EB2. As of July 31, 2021, 126 patients were available for the assessment of treatment results. After a median follow up of 9.6 months, median number of courses on treatment was 4 courses (range, 1-14), 61 in DEC plus ATRA arm and 65 in DEC arm . OR was achieved in 85.2% of DEC plus ATRA patients compared to 56.9% in DEC monotherapy (p<0.001). mCR rate was 73.8% in patients treated with DEC plus ATRA and 53.8% in those with DEC monotherapy (p=0.02). HI rate was 63.9% and 44.6% in patients with DEC plus ATRA and DEC monotherapy, respectively (p=0.03). The median OS and PFS were 18.8 months and 13.5 months for DEC plus ATRA arms, 19.2 months and 13.0 months for in DEC arm, respectively. 72.7% patients developed at least one adverse event (AE) during the trial, 73.3% in the DEC plus ATRA arm and 72.0% in DEC arm, respectively. Grade 3/4 Hematological toxicity occurred in 73.68 % of DEC plus ATRA arm and 76.92 % of DEC arm. Hyperlipidemia occurred in 31 patients in DEC plus ATRA arm (3.2% grade 3/4), and 18 (no grade 3/4) in DEC arm (p<0.001). Incidence of headache was higher in DEC plus ATRA arm (14.7% vs 4.0% in DEC arm, respectively, p<0.001). No other statistically significant differences were observed in the incidence of treatment-related AEs between the two groups. No early death occurred. Conclusion: Combination of DEC and ATRA achieved an OR rate of 85.2% in MDS subtype EB. Enrollment is ongoing to assess its efficacy and safety in treating EB. This therapy may be a new treatment option for EB subjects. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

FAB classification of myelodysplastic syndromes: merits and controversies

1995 ◽  
Vol 71 (1) ◽  
pp. 3-11 ◽  
Author(s):  
G. E. G. Verhoef ◽  
S. Pittaluga ◽  
C. De Wolf-Peeters ◽  
M. A. Boogaerts
Keyword(s):  
Myelodysplastic Syndromes ◽  
Fab Classification

Sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (HCC): Safety and efficacy in Child-Pugh (CP) class A and B patients.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 306-306
Author(s):  
Tiziana Pressiani ◽  
Corrado Boni ◽  
Lorenza Rimassa ◽  
Roberto Labianca ◽  
Stefano Fagiuoli ◽  
...  
Keyword(s):  
Descriptive Analysis ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Safety And Efficacy ◽  
Advanced Hcc ◽  
Class A ◽  
Tolerability Data ◽  
Prospective Trials ◽  
Open Label Trial ◽  
Grade 3

306 Background: S is the first systemic agent that has been shown to prolong survival in pts with CP A advanced HCC. However, its safety and efficacy have not been extensively evaluated in pts with CP B cirrhosis. Methods: We performed a descriptive analysis on pts with histologically documented advanced HCC and CP A/B cirrhosis, enrolled in a multicenter phase II randomized, open-label trial (data reported elsewhere), in order to assess the feasibility and efficacy of treatment with S in CP B pts. Written informed consent was obtained from all pts. Results: From April 2007 to July 2008, 297 pts were prospectively treated with S 400 mg bid, 234 (78.8%) CP A, 63 (21.2%) CP B. 232 pts were male (76%), median age was 68.3 yrs (range 19.8-89.2 yrs), 217 pts had no extra hepatic disease (73.1%). The two subgroups, according to CP class A or B, were homogeneous for all considered parameters. Median treatment duration was >3 months (mos) for 59.4% of CP A pts and for 27% of CP B pts (p <0.001). Median PFS for the total population was 3.9 mos, 4.3 mos for CP A pts and 2.1 mos for CP B pts (p<0.001). Median OS was 10 mos for CP A pts and 3.8 mos for CP B pts (p<0.001). Adverse events (all grades) were similar in type and incidence for CP A and B pts, with fatigue, stomatitis, diarrhea and weight loss having the highest incidence (44%, 41%, 38% and 38%, respectively). Specifically, no differences in terms of grade 3-4 events have been documented between the two groups. Conclusions: This study supports the feasibility of S also in advanced HCC pts with CP B status. Tolerability data suggest that pts with CP B status might potentially be treated safely with S for its potential survival benefits. Further prospective trials, specifically designed to investigate S in CP B pts, are eagerly advocated.

Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined non-small cell lung cancer (NSCLC) patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8063-8063 ◽  
Author(s):  
Jacques De Greve ◽  
Teresa Moran ◽  
Marie-Pascale Graas ◽  
Daniella Galdermans ◽  
Peter Vuylsteke ◽  
...  
Keyword(s):  
Objective Response ◽  
Open Label ◽  
Erbb Family ◽  
Prior Therapy ◽  
Erbb Family Blocker ◽  
Open Label Trial ◽  
Never Smokers ◽  
Grade 3 ◽  
Nsclc Patients ◽  
Egfr Tkis

8063 Background: EGFR mutation+ (M+) NSCLC pts have an improved response to EGFR TKIs vs non-M+ pts. Data on EGFR FISH+ (gene amplified) and HER2 M+ pts are, however, limited. Afatinib is an irreversible ErbB Family Blocker with efficacy in Ph II/III trials in EGFR M+ NSCLC. This exploratory, open-label trial assessed afatinib in 3 genotypically and demographically defined NSCLC groups. Methods: Never/ex-smokers with stage IIIB/IV lung adenocarcinoma with EGFR M+ tumors who had failed prior EGFR TKIs, HER2 M+ tumors independent of prior therapy, or EGFR FISH+ tumors who received ≤3 prior chemotherapies were enrolled. Afatinib 50 mg qd was administered until disease progression or intolerable adverse events. Tumor assessments (RECIST 1.0) were performed every 8 wks. Pts who progressed on afatinib but experienced clinical benefit could continue treatment with afatinib 40 mg qd + paclitaxel 80 mg/m² qw on days 1, 8 and 15 every 28-day cycle. Primary endpoint: Confirmed objective response. Results: 41 pts were treated: 63% female; median age 63 yrs; 68% never smokers; 32% ex-smokers. 33 pts received afatinib monotherapy only; 8 pts received afatinib followed by afatinib/paclitaxel combination therapy. 78% (n=32) of pts were EGFR M+, 5% (n=2) were EGFR FISH+ and 17% (n=7) were HER2 M+. For afatinib monotherapy, 1 confirmed partial response (PR) was observed (EGFR FISH+), stable disease (SD) was seen in 5/7 HER2 M+, 2/2 EGFR FISH+ and 17/32 EGFR M+ pts, and overall disease control (DC) rate was 59% (n=24); mean duration of DC was 26 wks.Median PFS was 16 wks (17 wks in HER2 M+ pts). Of 8 afatinib/paclitaxel-treated pts, 1 had a confirmed PR and 2 had SD; median PFS was 7 wks. Most frequently reported drug-related AEs in afatinib monotherapy pts were diarrhea (n=39; grade ≥3 n=13), rash/acne (n=33; grade ≥3 n=4) and stomatitis (n=19; grade ≥3 n=2). In the combination arm these were diarrhea (n=4; grade ≥3 n=1) and nausea (n=3; grade ≥3 n=0). Conclusions: Efficacy of afatinib in EGFR M+ NSCLC pts has been established in previous trials. Novel activity of afatinib in HER2 M+ and EGFR FISH+ NSCLC pts has been demonstrated here, with a manageable safety profile of afatinib in the overall population. Clinical trial information: NCT00730925.

Hematologic Response to Three Alternative Dosing Schedules of Azacitidine in Patients With Myelodysplastic Syndromes

2009 ◽  
Vol 27 (11) ◽  
pp. 1850-1856 ◽  
Author(s):  
Roger M. Lyons ◽  
Thomas M. Cosgriff ◽  
Sanjiv S. Modi ◽  
Robert H. Gersh ◽  
John D. Hainsworth ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Refractory Anemia ◽  
Open Label ◽  
Open Label Study ◽  
Transfusion Independence ◽  
Dosing Regimens ◽  
Grade 3 ◽  
Myelomonocytic Leukemia ◽  
Rbc Transfusion

Purpose Azacitidine (AZA) is effective treatment for myelodysplastic syndromes (MDS) at a dosing schedule of 75 mg/m2/d subcutaneously for 7 days every 4 weeks. The initial phase of this ongoing multicenter, community-based, open-label study evaluated three alternative AZA dosing schedules without weekend dosing. Patients and Methods MDS patients were randomly assigned to one of three regimens every 4 weeks for six cycles: AZA 5-2-2 (75 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 75 mg/m2/d for 2 days); AZA 5-2-5 (50 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 50 mg/m2/d for 5 days); or AZA 5 (75 mg/m2/d subcutaneously for 5 days). Results Of patients randomly assigned to AZA 5-2-2 (n = 50), AZA 5-2-5 (n = 51), or AZA 5 (n = 50), most were French-American-British (FAB) lower risk (refractory anemia [RA]/RA with ringed sideroblasts/chronic myelomonocytic leukemia with < 5% bone marrow blasts, 63%) or RA with excess blasts (30%), and 79 (52%) completed ≥ six treatment cycles. Hematologic improvement (HI) was achieved by 44% (22 of 50), 45% (23 of 51), and 56% (28 of 50) of AZA 5-2-2, AZA 5-2-5, and AZA 5 arms, respectively. Proportions of RBC transfusion–dependent patients who achieved transfusion independence were 50% (12 of 24), 55% (12 of 22), and 64% (16 of 25), and of FAB lower-risk transfusion-dependent patients were 53% (nine of 17), 50% (six of 12), and 61% (11 of 18), respectively. In the AZA 5-2-2, AZA 5-2-5, and AZA 5 groups, 84%, 77%, and 58%, respectively, experienced ≥ 1 grade 3 to 4 adverse events. Conclusion All three alternative dosing regimens produced HI, RBC transfusion independence, and safety responses consistent with the currently approved AZA regimen. These results support AZA benefits in transfusion-dependent lower-risk MDS patients.

A Phase II Study Of V-BEAM (Bortezomib, Carmustine, Etoposide, Cytarabine, and Melphalan) As Conditioning Regimen Prior To Second Autologous Stem Cell Transplantation For Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5492-5492 ◽  
Author(s):  
Tzu-Fei Wang ◽  
Mark A. Fiala ◽  
Ningying Wu ◽  
Theresa Fletcher ◽  
Camille N. Abboud ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Clostridium Difficile ◽  
Median Duration ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Response Rates ◽  
Grade 3 ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Background High-dose melphalan (HDM) has been the standard conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) for decades. Second ASCT is often offered as salvage therapy for patients who relapse after a first ASCT, but while response rates are similar, the progression free survival (PFS) is rarely comparable with that of the first ASCT when HDM conditioning is used for both. BEAM (carmustine, etoposide, cytarabine, and melphalan) is one of the most commonly used conditioning regimens for lymphoma patients undergoing ASCT and all of the components have been shown to be effective in refractory MM, but it has not been tested as a conditioning regimen for ASCT in MM. Bortezomib has been incorporated with HDM as a conditioning regimen for initial ASCT, with promising outcomes and limited toxicities. Based on these findings, we proposed a new conditioning regimen, V-BEAM (bortezomib-BEAM), administered prior to a second ASCT for relapsed/progressive MM, aiming to improve the response rates and PFS of the second ASCT. Objectives To evaluate the safety and efficacy of a new conditioning regimen, V-BEAM, prior to a second ASCT in patients with relapsed/progressive MM after a first ASCT with HDM conditioning. Patient/Methods Patients with relapsed/progressive MM after a previous ASCT with HDM conditioning were enrolled after 2 to 6 cycles of induction chemotherapy with a bortezomib or carfilzomib based regimen. Patients who had progressive disease on induction chemotherapy were excluded. V-BEAM was administered as the following: Bortezomib 1.3 mg/m2 on days -6, -3, +1, and +4, carmustine 300 mg/m2 on day -7, etoposide 100 mg/m2 and cytarabine 100 mg/m2 each twice daily on days -6 through -3, and melphalan 140 mg/m2 on day -2. On day 0, autologous stem cells (> 2.0x106/kg) were infused. No maintenance or consolidation therapy was given post-transplant. Results A total of 10 patients were enrolled from October 2012 to May 2013 at the Siteman Cancer Center. The median age was 64.5 years old (range, 48-68) and 50% were male. Seventy percent of patients were Durie-Salmon stage IIIA at diagnosis, while the remaining 30% were stage IIA. The median time to progression following previous autologous stem cell transplant was 29 months (range, 17-97). The median number of prior therapies (including first ASCT) was 4 (range, 3-6). At the time of abstract submission, one patient has not reached day +100 and two patients expired within 30 days of transplant. For the remaining seven patients, the day +100 response rates include five complete responses (CR) and two very good partial responses (VGPR). To date, no patients have had subsequent disease progression after a median follow-up of 5.0 months (range, 2.3-9.3). Two patients suffered from treatment related mortality (one from neutropenic colitis [Day +18] and the other from sepsis [Day +2]). Serious complications included: neutropenic fevers (100%), diarrhea (grade 3-4, 100%), oral mucositis (all grade, 100%; grade 3-4, 20%), sepsis (30%), Clostridium difficile colitis (30%), and neutropenic colitis without Clostridium difficile (30%). Two patients (20%) had new or worsening peripheral neuropathy, both of which were grade 2 and easily controlled. The median duration of hospitalization was 23 days (range, 19-29). The median duration of neutrophil engraftment and platelet engraftment (>20x109/L) were 10 days (range, 9-11) and 22.5 days (range, 17-36), respectively. The median duration of intravenous antibiotics was 14 days (range, 2-23). Two patients were readmitted shortly following discharge for neutropenic fevers and candida esophagitis, respectively. In June 2013, eight months after study initiation, the decision was made to terminate the study due to excessive toxicity. Conclusion While the new conditioning regimen V-BEAM prior to a second ASCT produced promising response rates for relapsed/progressive MM, it resulted in unexpected treatment related mortality and should not be investigated further without modifications. Disclosures: Off Label Use: BEAM regimen as a conditioning regimen for relapsed multiple myeloma. Abboud:Ariad, Alexion, Novartis, Teva: Honoraria, Speakers Bureau. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau. Vij:Celgene : Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau.

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