advertisement

fda_workshop_carroll

50 %
50 %
advertisement
Information about fda_workshop_carroll
Science-Technology

Published on January 12, 2009

Author: aSGuest10195

Source: authorstream.com

advertisement

Acute Lymphoblastic Leukemia : Acute Lymphoblastic Leukemia Minimal Residual Disease as a Surrogate Response Endpoint ASH/FDA Workshop Washington DC June 25, 2005 COG ALL Risk GroupsB-Precursor ALL : COG ALL Risk GroupsB-Precursor ALL NCI Risk Groups CNS Disease Trisomies 4, 10, & 17 TEL/AML 1 MLL BCR-ABL Chromosomes <44 Rapidity of Response MRD - End of Induction Low Risk Standard Risk High Risk Very High Risk Early Response : Early Response Takes into account host and tumor variables that influence sensitivity and resistance Prednisone “prephase” (BFM) Fall in peripheral blasts after one week of multiagent induction (St. Jude) Day 7 blast content in bone marrow (CCG) Slide 4: Historical Control(HC) CCG-1800s/1922 series vs. Current CCG-1950/60s(1956s) series EFS Outcome by Day 7 Marrow (Remission at End of Induction) 5 Year EFS: HC Current M1 80.4% 82.6% M2 74.0% 74.6% M3 67.9% 69.0% Probability Years Followed Slide 5: CCG-1882: Augmented Therapy Improves EFS for Patients with an SER (M3 Marrow at day 7) Probability Years Followed (from Randomization) 8-Year EFS RHR BFM 52.3%(s.d. 6.5%) 1.9 Augmented BFM 70.2%(s.d. 6.7%) Baseline Augmented BFM (n=155) BFM (n=156) Log Rank p=.0006 Nachman et al., NEJM 338: 1663-1671, 1998 DATA UPDATED DEC 2004 Assessment of Early Response: Integration of MRD into Clinical Trials : Assessment of Early Response: Integration of MRD into Clinical Trials Morphologic assessment is a crude, but accurate and reproducible way to identify patients likely to have good or bad outcomes PCR or flow cytometric assessment of MRD More sensitive and could be more accurate way to identify groups for risk-adapted therapy Results will vary based on: MRD timepoint analyzed Therapy prior to MRD analysis Sensitivity of MRD assay utilized Major Techniques Used to Assess MRD in Leukemia : Major Techniques Used to Assess MRD in Leukemia Flow cytometry detection of leukemia associated phenotypes Applicable in almost all cases Fast, relatively inexpensive Less sensitive than molecular methods Probably sensitive enough for identification of HR patients PCR amplification of antigen receptor loci (Ig or TCR) Applicable to ~80% of cases Laborious and expensive (10 x flow), but very sensitive Better for identification of LR patients?? PCR amplification of fusion transcripts only suitable for defined molecular subgroups such as Ph+ ALL (40%) Prognostic Significance of End Induction MRD: BFM-Austria : Prognostic Significance of End Induction MRD: BFM-Austria Many pilot studies show that MRD levels early in therapy are predictive of outcome .01%-.1% <.01% >0.1% Dworzak et al. Blood 99: 1952, 2002 N=17 Early Response : Early Response All studies show correlation between MRD and outcome AEIOP ALL 2000/ALL-BFM 2000: Risk Stratification : AEIOP ALL 2000/ALL-BFM 2000: Risk Stratification Standard risk group (SR) Prednisone good response + M1 day 33 AND Negative MRD (<10-4) at day 33 and week 12 AND No t(9;22) or t(4;11) Medium risk group (MR) Prednisone good response + M1 day 33 AND No t(9;22) or t(4;11) AND Not SR or HR on MRD criteria High risk group (HR) Prednisone poor response or not M1 day 33 OR t(9;22) or t(4;11) OR MRD >10-3 at week 12 Slide 11: MRD-SR .97, SE=.03 (N= 39, 1 event) MRD-MR .77, SE=.05 (N=160, 23 events) MRD-HR .38, SE=.06 (N=114, 57 events) AIEOP + ALL-BFM 2000, EFS (4 years) Risk Group HR 95 by MRD Risk Groups Pts enrolled Sep/Jul 00–Oct 04 (Status April 05) Data courtesy of Valentino Conter and Martin Schrappe Reducing Disease Burden Pre-Transplant Improves Outcomes : Reducing Disease Burden Pre-Transplant Improves Outcomes Uzunel et al. Blood 2001 Residual Disease Monitoring at End Induction: Flow Cytometry : Tumor Tumor Dx d29 POG ALinC17 to Date: > 2,000 samples received 95% compliance MRD Sensitivity 1/1000 - 1/10,000 24 hr turn around 28.6% of patients positive; Median .069% Residual Disease Monitoring at End Induction: Flow Cytometry End Induction Marrow 534/1937 (28%) of Cases Positive Overall : End Induction Marrow 534/1937 (28%) of Cases Positive Overall No. of cases + <.01 .01-.1 .1-1.0 1.0-10 >10 Percent Leukemic Cells Michael Borowitz Day 29 Flow MRD Correlates with NCI Risk Group : Day 29 Flow MRD Correlates with NCI Risk Group % MRD + MRD level Median .043% LR Median .14% HR Michael Borowitz Day 29 Flow MRD Correlates with Day 8 Morphologic Assessment of Response : Day 29 Flow MRD Correlates with Day 8 Morphologic Assessment of Response Day 8 Marrow Blasts % MRD + (n=1879) MRD level p<.001 Michael Borowitz Prognostic Significance of MRD - 9906 :  Prognostic Significance of MRD - 9906 n=79 n=156 Minimal Residual Disease 9906 : Minimal Residual Disease 9906 169 21 33 24 p=.0054 Challenges of Marrow Relapse : Challenges of Marrow Relapse Despite the success in treating newly diagnosed ALL, outcomes following marrow relapse remain poor Many relapses occur in favorable risk patients It is difficult to predict response to retrieval therapy Attempts to further intensify therapy have generally not led to improvements in outcome Obstacles to Successful Treatment for Relapsed ALL : Obstacles to Successful Treatment for Relapsed ALL Remission re-induction failures Early second relapse Regimen-related toxicity Remission Re-induction Rates : Remission Re-induction Rates Obstacles to Successful Treatment for Relapsed ALL : Obstacles to Successful Treatment for Relapsed ALL Depth of second CR is shallow 30-40% of patients who achieve a second remission develop an early subsequent recurrence Significant regimen-related toxicity Toxic death rates of 3-8% on average Further intensification likely to be of limited value Higher Risk Relapse: Common Therapeutic Approaches : Higher Risk Relapse: Common Therapeutic Approaches Early Marrow/T-cell Late Marrow/Early EM Chemotherapy Alt Donor SCT Matched Related Donor Transplant Common Re-induction Introduction of New Agents in Patients with Very High Risk of Treatment Failure : Introduction of New Agents in Patients with Very High Risk of Treatment Failure Re-induction Block 1 Re-induction Block 2 Reduction Phase VCR, Pred, PEG, Adr Re-induction Block 3 ARA-C, ASP CTX, VP-16, MTX VCR, Pred, PEG, Adr ARA-C, ASP CTX, VP-16, MTX MRD Time MRD MRD Epratuzumab Pilot I New Agent Pilot Correlate with 4 month EFS COG: AALL01P2 : BLOCK 1 BLOCK 2 BLOCK 3 VCR days 1,8,15,22 CTX days 1-5 ARA-C days 1,2,8,9 PRED days 1-29 VP-16 days 1-5 L-ASP days 2,9 PEG days 2,8,15,22 IT MTX (ITT) days 1,22 DOXO day 1 *HD MTX day 22 IT ARA-C day 1 (*count dependent) IT MTX days 15 ,29 (CNS -) ITT days 8,15,22,29 (CNS +) * Imatinib is also given in combination with chemotherapy for Ph+ relapse COG: AALL01P2 MRD Detection During Treatment of Relapse: AALL01P2 : MRD Detection During Treatment of Relapse: AALL01P2 Slide courtesy of Mike Borowitz, MD, PhD Correlation of MRD with Time of First Relapse: AALL01P2 : Correlation of MRD with Time of First Relapse: AALL01P2 Borowitz, et al. ASH 2004 Kinetics of MRD Response:Good Responders (34/46) : Kinetics of MRD Response:Good Responders (34/46) (n=15) (n=8) (n=11) Epratuzumab: Mechanism of Action : Epratuzumab: Mechanism of Action Highly selective for CD22 positive B-precursor and B-Cells Alters lymphocyte adhesion & homing Reacts across B-cell lymphoma subtypes Minimal activity with normal non-lymphoid tissues Mechanisms of action: Antibody-dependent cellular cytotoxicity Complement-mediated lysis 6 C-C 7 C-C 2 C-C 5 C-C 3 C-C 1 C-C 4 C-C Leonard and Link Seminars in Oncol 2002 CD22 Epratuzumab Carnahan et al Clin CA Res 2003 New Agent Initiatives: EpratuzumabADVL04P2 (Early Relapse) : New Agent Initiatives: EpratuzumabADVL04P2 (Early Relapse) Block 1 Block 2 Block 3 Triple Induction Phase 2 Block 1 Block 2 Block 3 Triple Induction Reduction Phase 6 dose levels Phase 1 E-mab MRD – Surrogate Endpoint : MRD – Surrogate Endpoint MRD Endpoints MRD + vs. MRD- End Induction Pre – BMT (after block 3) Median MRD Value Slope of MRD Reduction R1, R2, R3 Conclusions : Conclusions MRD is a Powerful Predictor of Outcome MRD Measurements Can be Integrated into Multi-institutional Trials MRD Can Be Used To Track Response to New Agents in the Context of Multiagent Re-induction Data Indicates That MRD can Be Used as an Endpoint to Assess Efficacy Prioritize New Agents for Conventional Trials Gain Accelerated Approval Acknowledgements : Steve Hunger Naomi Winick Elizabeth Raetz Michael Borowitz Acknowledgements

Add a comment

Related presentations