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Acute Lymphoblastic Leukemia

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Acute Lymphoblastic Leukemia

  1. 1. Acute Lymphoblastic Leukemia <ul><li>Minimal Residual Disease as a </li></ul><ul><li>Surrogate Response Endpoint </li></ul><ul><li>ASH/FDA Workshop </li></ul><ul><li>Washington DC </li></ul><ul><li>June 25, 2005 </li></ul>
  2. 2. COG ALL Risk Groups B-Precursor ALL <ul><li>NCI Risk Groups </li></ul><ul><li>CNS Disease </li></ul><ul><li>Trisomies 4, 10, & 17 </li></ul><ul><li>TEL/AML 1 </li></ul><ul><li>MLL </li></ul><ul><li>BCR-ABL </li></ul><ul><li>Chromosomes <44 </li></ul><ul><li>Rapidity of Response </li></ul><ul><li>MRD - End of Induction </li></ul>Low Risk Standard Risk High Risk Very High Risk
  3. 3. Early Response <ul><li>Takes into account host and tumor variables that influence sensitivity and resistance </li></ul><ul><ul><li>Prednisone “prephase” (BFM) </li></ul></ul><ul><ul><li>Fall in peripheral blasts after one week of multiagent induction (St. Jude) </li></ul></ul><ul><ul><li>Day 7 blast content in bone marrow (CCG) </li></ul></ul>
  4. 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
  5. 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
  6. 6. Assessment of Early Response: Integration of MRD into Clinical Trials <ul><li>Morphologic assessment is a crude, but accurate and reproducible way to identify patients likely to have good or bad outcomes </li></ul><ul><li>PCR or flow cytometric assessment of MRD </li></ul><ul><ul><li>More sensitive and could be more accurate way to identify groups for risk-adapted therapy </li></ul></ul><ul><li>Results will vary based on: </li></ul><ul><ul><li>MRD timepoint analyzed </li></ul></ul><ul><ul><li>Therapy prior to MRD analysis </li></ul></ul><ul><ul><li>Sensitivity of MRD assay utilized </li></ul></ul>
  7. 7. Major Techniques Used to Assess MRD in Leukemia <ul><li>Flow cytometry detection of leukemia associated phenotypes </li></ul><ul><ul><li>Applicable in almost all cases </li></ul></ul><ul><ul><li>Fast, relatively inexpensive </li></ul></ul><ul><ul><li>Less sensitive than molecular methods </li></ul></ul><ul><ul><ul><li>Probably sensitive enough for identification of HR patients </li></ul></ul></ul><ul><li>PCR amplification of antigen receptor loci (Ig or TCR) </li></ul><ul><ul><li>Applicable to ~80% of cases </li></ul></ul><ul><ul><li>Laborious and expensive (10 x flow), but very sensitive </li></ul></ul><ul><ul><ul><li>Better for identification of LR patients?? </li></ul></ul></ul><ul><li>PCR amplification of fusion transcripts only suitable for defined molecular subgroups such as Ph + ALL (40%) </li></ul>
  8. 8. Prognostic Significance of End Induction MRD: BFM-Austria <ul><li>Many pilot studies show that MRD levels early in therapy are predictive of outcome </li></ul>.01%-.1% <.01% >0.1% Dworzak et al. Blood 99: 1952, 2002 N=17
  9. 9. Early Response <ul><li>All studies show correlation between MRD and outcome </li></ul>26% to 28% 5% to 16% > 10 -2 20% to 42% < 10 -3 > 90% 42% to 75% No MRD EFS (3 year) Percent of Patients End Induction MRD
  10. 10. AEIOP ALL 2000/ALL-BFM 2000: Risk Stratification <ul><li>Standard risk group (SR) </li></ul><ul><ul><li>Prednisone good response + M1 day 33 AND </li></ul></ul><ul><ul><li>Negative MRD (<10 -4 ) at day 33 and week 12 AND </li></ul></ul><ul><ul><li>No t(9;22) or t(4;11) </li></ul></ul><ul><li>Medium risk group (MR) </li></ul><ul><ul><li>Prednisone good response + M1 day 33 AND </li></ul></ul><ul><ul><li>No t(9;22) or t(4;11) AND </li></ul></ul><ul><ul><li>Not SR or HR on MRD criteria </li></ul></ul><ul><li>High risk group (HR) </li></ul><ul><ul><li>Prednisone poor response or not M1 day 33 OR </li></ul></ul><ul><ul><li>t(9;22) or t(4;11) OR </li></ul></ul><ul><ul><li>MRD >10 -3 at week 12 </li></ul></ul>
  11. 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 years p: 1-2 .05 1-3 .0001 2-3 .0001 dsmc0405.tab 13APR05 P 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5
  12. 12. Reducing Disease Burden Pre-Transplant Improves Outcomes Uzunel et al. Blood 2001
  13. 13. 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%
  14. 14. 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
  15. 15. Day 29 Flow MRD Correlates with NCI Risk Group % MRD + MRD level Median .043% LR Median .14% HR Michael Borowitz
  16. 16. 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
  17. 17. Prognostic Significance of MRD - 9906 n=79 n=156 EVENT-FREE SURVIVAL 0 20 40 60 80 100 0 1 2 3 4 5 Years Probability (%) MRD>.01% MRD Negative p-value=0.00304
  18. 18. Minimal Residual Disease 9906 169 21 33 24 p=.0054
  19. 19. Challenges of Marrow Relapse <ul><li>Despite the success in treating newly diagnosed ALL, outcomes following marrow relapse remain poor </li></ul><ul><ul><li>Many relapses occur in favorable risk patients </li></ul></ul><ul><ul><li>It is difficult to predict response to retrieval therapy </li></ul></ul><ul><ul><li>Attempts to further intensify therapy have generally not led to improvements in outcome </li></ul></ul>
  20. 20. Obstacles to Successful Treatment for Relapsed ALL <ul><li>Remission re-induction failures </li></ul><ul><li>Early second relapse </li></ul><ul><li>Regimen-related toxicity </li></ul>
  21. 21. Remission Re-induction Rates Remission induction/re-induction rates ~ 75% Early marrow relapse > 90% Late marrow relapse > 98% Newly diagnosed ALL
  22. 22. Obstacles to Successful Treatment for Relapsed ALL <ul><li>Depth of second CR is shallow </li></ul><ul><ul><li>30-40% of patients who achieve a second remission develop an early subsequent recurrence </li></ul></ul><ul><li>Significant regimen-related toxicity </li></ul><ul><ul><li>Toxic death rates of 3-8% on average </li></ul></ul><ul><ul><li>Further intensification likely to be of limited value </li></ul></ul>
  23. 23. 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 Block 1 Block 2 Block 3 Early Marrow Late Marrow Early CNS Early Testicular
  24. 24. 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
  25. 25. <ul><li>BLOCK 1 BLOCK 2 BLOCK 3 </li></ul><ul><li>VCR days 1,8,15,22 CTX days 1-5 ARA-C days 1,2,8,9 </li></ul><ul><li>PRED days 1-29 VP-16 days 1-5 L-ASP days 2,9 </li></ul><ul><li>PEG days 2,8,15,22 IT MTX (ITT) days 1,22 </li></ul><ul><li>DOXO day 1 *HD MTX day 22 </li></ul><ul><li>IT ARA-C day 1 (*count dependent) </li></ul><ul><li>IT MTX days 15 ,29 (CNS -) </li></ul><ul><li>ITT days 8,15,22,29 (CNS +) </li></ul><ul><li>* Imatinib is also given in combination with chemotherapy for Ph+ relapse </li></ul>COG: AALL01P2
  26. 26. AALL01P2 Study Design Continuation Therapy MRD ARM A MRD MRD Block 2 MRD MRD ARM B Block 2 MRD Block 1 Block 1 Block 3 Block 3 On Study Randomization CNS + patients non-randomly assigned to ARM B DNA Arrays DNA Arrays
  27. 27. MRD Detection During Treatment of Relapse: AALL01P2 Slide courtesy of Mike Borowitz, MD, PhD 0.34% 16/46 (35%) 3 <ul><ul><li>0.19% </li></ul></ul>31/63 (49%) 2 0.73% 66/101(65%) 1 Median MRD level MRD+ Time Point
  28. 28. Correlation of MRD with Time of First Relapse: AALL01P2 Borowitz, et al. ASH 2004 .01 3/19 (16%) 9/15 (60%) 3 .009 9/21 (43%) 18/22 (82%) 2 .018 14/29 (48%) 31/41 (76%) 1 p value MRD+ Late Relapse MRD+ Early Relapse Time Point
  29. 29. Kinetics of MRD Response: Good Responders (34/46) (n=15) (n=8) (n=11)
  30. 30. Epratuzumab: Mechanism of Action <ul><li>Highly selective for CD22 positive B-precursor and B-Cells </li></ul><ul><li>Alters lymphocyte adhesion & homing </li></ul><ul><li>Reacts across B-cell lymphoma subtypes </li></ul><ul><li>Minimal activity with normal non-lymphoid tissues </li></ul><ul><li>Mechanisms of action: </li></ul><ul><ul><ul><li>Antibody-dependent cellular cytotoxicity </li></ul></ul></ul><ul><ul><ul><li>Complement-mediated lysis </li></ul></ul></ul>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 Human IgG1 Murine CDRs
  31. 31. New Agent Initiatives: Epratuzumab ADVL04P2 (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 Response
  32. 32. MRD – Surrogate Endpoint <ul><li>MRD Endpoints </li></ul><ul><ul><li>MRD + vs. MRD- </li></ul></ul><ul><ul><ul><li>End Induction </li></ul></ul></ul><ul><ul><ul><li>Pre – BMT (after block 3) </li></ul></ul></ul><ul><ul><li>Median MRD Value </li></ul></ul><ul><ul><li>Slope of MRD Reduction </li></ul></ul><ul><ul><ul><li>R1, R2, R3 </li></ul></ul></ul>
  33. 33. Conclusions <ul><li>MRD is a Powerful Predictor of Outcome </li></ul><ul><li>MRD Measurements Can be Integrated into Multi-institutional Trials </li></ul><ul><li>MRD Can Be Used To Track Response to New Agents in the Context of Multiagent Re-induction </li></ul><ul><li>Data Indicates That MRD can Be Used as an Endpoint to Assess Efficacy </li></ul><ul><ul><li>Prioritize New Agents for Conventional Trials </li></ul></ul><ul><ul><li>Gain Accelerated Approval </li></ul></ul>
  34. 34. Acknowledgements Steve Hunger Naomi Winick Elizabeth Raetz Michael Borowitz

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