SPIRIT3 support includes Biobanking: broadly as for SPIRIT2, but plus genomic DNA (mouth wash via kit) Correlative Science: Biomarkers LSC biology NGS:

Slides:

Advertisements

Similar presentations

Dr N M Butt Consultant Haematologist

Advertisements

A Proposal for BMS (Dasatinib) in GIST Jon Trent, MD, PhD Assistant Professor Dept. of Sarcoma Medical Oncology The University of Texas, M. D. Anderson.

The National CML Society 2012 CML UPDATE “What’s New? What’s Coming?” Luke Akard MD Co-Director Indiana Blood and Marrow Transplantation Program.

Chronic Myeloid Leukemia: Treatment Success and Milestones

Final Study Results of the Phase III Dasatinib versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA )1.

Herceptin® (trastuzumab) in combination with chemotherapy: pivotal metastatic breast cancer survival data 1.

Update on the Side Effects of Tyrosine Kinase Inhibitors

Monitoring CML Treatment: Addressing the Issues for the Community Hematologist/Oncologist Hagop M. Kantarjian, MD Chairman; Professor, Department of Leukemia.

Comparison of PI vs PI  ATV/r vs DRV/rATADAR. ATV/r 300/100 mg + TDF/FTC qd N = 91 N = 89 DRV/r 800/100 mg + TDF/FTC qd  Design Randomisation 1: 1 Open-label.

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Target

BEAUTI f UL: morBidity-mortality EvAlUaTion of the I f inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction Purpose.

New Agents Heather Kertland, PharmD.

Copyright © 2011 Research To Practice. All rights reserved. Interest in Topics Related to the Treatment of Patients with CML (Percent Responding 9 or 10)

Comparison of Nilotinib and Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd Beyond One Year Larson.

CML SPIRIT 3 Steve O’Brien Northern Institute for Cancer Research Newcastle University Medical School Newcastle, March 2013.

Treatment of CML Transplant or Imatinib? Mark B Juckett MD Section of Hematology/BMT University of Wisconsin.

Ponatinib as Initial Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Cortes JE et al. Proc ASH 2013;Abstract 1483.

What are the risks and benefits of Tyrosine Kinase Inhibitors ? Wendy Osborne Consultant Haematologist Freeman Hospital, Newcastle.

Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients: Initial Results of a Multicenter, Open Label.

Steady-State Plasma Imatinib Levels in 142 GIST Patients Distribution, Dose, Dose Escalation, and Response Laura K Nolden 1, Linyee Shum 2, Amaury Dumont.

ENESTnd Update: Nilotinib (NIL) vs Imatinib (IM) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and the Impact.

A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Updated.

David Marin, Imperial College London Early molecular prediction of response to TKI.

CML TKIs – where are we up to? Steve O’Brien

Two Year Estimate of Overall Survival in COMBI-v, a Randomized, Open-Label, Phase 3 Study Comparing the Combination of Dabrafenib and Trametinib With Vemurafenib.

AI Study  Design SOF 1W then DCV + SOF 23W DVC + SOF Randomisation* 1 : 1 : 1 Open-label AI Study: DCV + SOF + RBV for genotypes 1, 2 and.

Gemcitabine + Cisplatin +/- Bevacizumab as 1st-line Treatment of Advanced NSCLC: AVAiL Study Manegold PASCO 25:#7514, 2007/Ann.

ENESTnd 24-Month Update: Continued Superiority of Nilotinib versus Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase.

An Ongoing Phase 3 Study of Bosutinib (SKI-606) versus Imatinib in Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Gambacorti-Passerini.

Final Analysis of Overall Survival for the Phase III CONFIRM Trial: Fulvestrant 500 mg versus 250 mg Di Leo A et al. Proc SABCS 2012;Abstract S1-4.

Ruan J et al. Proc ASH 2013;Abstract 247.

Epic: A Phase 3 Trial of Ponatinib Compared with Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CP-CML) Lipton JH.

Long Term Follow-up on the Treatment of High Risk Smoldering Myeloma with Lenalidomide plus Low Dose Dex (Rd) (Phase III Spanish Trial): Persistent Benefit.

ELITE - II Study Design  60 yrs; NYHA II - IV; EF  40 % ACEI naive or  7 days in 3 months prior to entry Standard Rx ( ± Dig / Diuretics ), ß - blocker.

Dasatinib Compared to Imatinib in Patients with Newly Diagnosed Chronic Myelogenous Leukemia in Chronic Phase (CML-CP): Twelve- Month Efficacy and Safety.

Initial Findings from the PACE Trial: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib,

Switching to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase with Suboptimal Cytogenetic Response on Imatinib: Results from the LASOR.

until tumour progression until tumour progression

Charlotte Kragelund et al N Engl J Med 2005;352: Baseline Clinical Characteristics According to Quartiles of NT-pro-BNP.

Phase II Trial of R-CHOP plus Bortezomib Induction Therapy Followed by Bortezomib Maintenance for Previously Untreated Mantle Cell Lymphoma: SWOG 0601.

Nilotinib versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP):

Dasatinib or Imatinib (IM) in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Two-Year Follow-Up from DASISION Kantarjian H et al.

Brentuximab Vedotin in Combination with RCHOP as Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 Study Yasenchak CA et al. Proc.

Acknowledgements Trial & data management, Newcastle Corinne Hedgley, Lynn Seeley, Caroline Hodgson, Ruth Bescoby, Carrie Page, Angela Fallows, Laura Brown,

Future of CML treatments – Are they getting us closer to cure? Andreas Hochhaus Universitätsklinikum Jena, Germany.

Working Groups in Chronic Myelogenous Leukemia: Choice of First-line Therapy This program is supported by an educational grant from.

Update on Approved TKIs Jorge Cortes, MD Chief, CML and AML Sections Department of Leukemia MD Anderson Cancer Center Houston, Texas.

Results from the International, Randomized Phase 3 Study of Ibrutinib versus Chlorambucil in Patients 65 Years and Older with Treatment-Naïve CLL/SLL (RESONATE-2TM)1.

Palumbo A et al. Proc ASH 2012;Abstract 200.

Shah N et al. Proc ASH 2010;Abstract 206.

Early Molecular and Cytogenetic Response Predict for Better Outcomes in Untreated Patients with CML-CP — Comparison of 4 TKI Modalities (Standard- and.

Echocardiographic modalities for evaluation and risk stratification of heart failure patients. 3D indicates 3-dimensional; EF, ejection fraction; LA, left.

Cortes JE et al. Proc ASCO 2010;Abstract 6502.

Great Debates and Updates in Hematologic Malignancies 2014

Barrios C et al. SABCS 2009;Abstract 46.

Chronic Myelogenous Leukemia Diagnosis and Treatment

Best Practices in Chronic Myeloid Leukemia by Multidisciplinary Teams

Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study by Neil P. Shah, François.

G. Michael Felker et al. JCHF 2014;2:

Johannes Steiner et al. JACC 2017;70:

Mirnela Byku, and Douglas L. Mann BTS 2016;1:95-106

Great Debates-CML Omacetaxine succinate

Crossover for pts meeting ELN 2013 failure criteria

1Kantarjian HM et al. Lancet Oncol 2011;12:

Leber B et al. Proc ASH 2013;Abstract 94.

Cumulative survival without events during 1 year in patients with preserved systolic function (left ventricular ejection fraction (LVEF) >40%) and with.

Associations between β-blocker dosage group, predischarge heart rate group, and the primary composite outcome of death or cardiovascular rehospitalisation.

Kantarjian HM et al. Blood 2008;112:Abstract 635.

Time to first event analysis revealed a significant difference in estimated event-free (death or hospitalisation) survival between patients with left ventricular.

Patient selection process in the present study.

Presentation transcript:

SPIRIT3 support includes Biobanking: broadly as for SPIRIT2, but plus genomic DNA (mouth wash via kit) Correlative Science: Biomarkers LSC biology NGS: mutation analysis : hypothesis generation

Example: Imatinib Metabolism NQO1 &2 TXN CYP3A4/5 St John’s Wort carbamazepine phenytoin ketoconazole erythromycin grapefruit juice minor metabolites CYPs: 1A1, 1B1, 1A2, 2D6, 2C9, 2C19 imatinib (t ½ = 18hrs) CGP (t ½ = 40hrs) EXCRETION ROS GSTs NATs, UGTs DNA damage cell damage

T1 v M1 v T1+M1 v none Time to CCR0.255 Overall Survival0.273 Treatment Failure0.041 Treatment Failure and Intolerance< Progression Free Survival (PFS)0.029 Event Free Survival (EFS)0.047 Mantel-Cox Log Rank Test (p values) p < n = 11 n = 17 n = 88 n = 77 GSTT1{del} and GSTM1{del} Results Davies et al 2012, EHA Amsterdam (abstract)

Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282) RANDOMISED*RANDOMISED* Nilotinib 400 mg BID (n = 281) N = centres 35 countries * Stratification by Sokal risk score. 10 years of follow-up are planned Primary endpoint = MMR at 12 months. This is superior in nilotinib recipients (either dose) compared with imatinib (P <.0001; Saglio et al NEJM 2010 ). ENESTnd: Study Design Kantarjian HM, et al. Blood. 2012;120(21):[abstract 1676].

Arterial Events by 3 Years (All Grades) Patients, n (%) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 IHD9 (3.2)11 (4.0)3 (1.1) PAOD4 (1.4)3 (1.1)0 11/23 IHD events occurred between years 2 and 3 (4 on nilotinib 300 mg BID, 5 on nilotinib 400 mg BID, 2 on imatinib) 3 patients on nilotinib 400 mg BID discontinued study drug due to IHD 2/7 PAOD events occurred between years 2 and 3; both occurred on nilotinib 400 mg BID 6/7 patients (85%) with PAOD had pre-existing risk factors at baseline No patient discontinued because of PAOD No patient at any time on study in either nilotinib arm had a QTcF > 500 ms or LVEF < 45% IHD, ischaemic heart disease; PAOD, peripheral arterial occlusive disease. 5 LVEF, left ventricular ejection fraction. Data cutoff: 27Jul2011.

ENESTnd: arterial Events by 4 Years Patients, n (%) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 IHD (3 yrs in brackets)11 (9)14 (11)3 (3) PAOD (3 yrs in brackets)4 (4)5 (3)0  Between years 3 and 4, five new patients had an IHD event (2 in the nilotinib 300 mg BID arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event (both in the nilotinib 400 mg BID arm)  1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly reported drug-related SAE (arterial stenosis limb) leading to treatment discontinuation Including cerebrovascular events: Data cutoff: 27Jul 2012.