OHSU Updates in Hematology and Breast Cancer Conference CML ASH Update - PowerPoint PPT Presentation

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  1. OHSU Updates in HematologyandBreast Cancer ConferenceCML ASH Update Michael J. Mauro, MD

  2. CML Abstracts Novel Agents Abstract # 109: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib or with the T315I Mutation Abstract # 601: A Phase 1 Study of DCC-2036, a Novel Oral Inhibitor of BCR-ABL1 Kinase, in Patients with Ph+ Leukemia, including Patients withT315I Mutation Path to Cure Abstract # 604: Discontinuation of Dasatinib or Nilotinib in Chronic Myeloid Leukemia Patients with Stable Undetectable BCR-ABL Transcripts: Results from the French CML Group Response Prediction Abstract # 112: Validation of the New ELN Recommendations for BCR-ABL KD Mutation Analysis in CML: an Analysis of the CML GIMEMA WP Studies Abstract # 783:Molecular and Cytogenetic Response at 3 MonthsofImatinibPredicts Progression-freeSurvival (PFS) and Overall Survival (OS) – a Follow-Up Analysis oftheRandomized CML-Study IV Longer-Term Follow-Up Abstract # 452: Nilotinib versus Imatinib in Patients with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 3-Year Follow-Up Abstract # 455 : Bosutinib versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia-- BELA Trial: 24-Month Follow-up

  3. Abstract #109

  4. Abstract #601

  5. DISCONTINUATION OF DASATINIB OR NILOTINIB IN CHRONIC MYELOID LEUKEMIA PATIENTS WITH STABLE UNDETECTABLE BCR-ABL TRANSCRIPTS:Results from the French CML group (FI-LMC) Delphine Rea*, Philippe Rousselot, Franck Nicolini, Laurence Legros, Michel Tulliez, Stéphane Giraudier, Pascale Cony-Makhoul, François Guilhot, François-Xavier Mahon Abstract #604 Selected by the ASH Program Session Name: 632. Chronic Myeloid Leukemia - Therapy: New Drugs, New Procedures Session Date: Monday, December 12, 2011 Session Time: 2:45 PM - 4:15 PM Presentation Time: 3:30 PM Room: San Diego Convention Center, Ballroom 20BC

  6. DESIGN AND ENDPOINTS D1 M6 M12 M18 M24 • Primary endpoint: stable MMR by 6 months • Main secondary endpoints: • Stable MMR by 12, 18 and 24 months • Risk of progression to AP/BP • Undetectable BCR-ABL by 12 months upon reintroduction of treatment Undetectable BCR-ABL ≥ 24 months STOP 2G-TKI Monthly RQ-PCR RQ-PCR every 2-3 months

  7. Trial Details: ELIGIBILITY MONITORING AND TREATMENT RESUMPTION POLICY Blood counts and RQ-PCR monthly during the first 12 months, and every 2-3 months thereafter Bone marrow smears, cytogenetic and mutational analysis recommended in case of a rise in BCR-ABL above 1% IS 2G-TKI reintroduction triggered by the loss of MMR (BCR-ABL/ABL ratio > 0.1% IS) • Age ≥ 18 years • CP- or AP-CML at diagnosis • M-BCR transcripts • Ongoing dasatinib or nilotinib treatment • No prior progression to AP/BC while on therapy • Treatment with TKI for at least 36 months • Undetectable BCR-ABL* for at least 24 months * Undetectable BCR-ABL at local laboratories with at least 20 000x2 copies of the ABL1 control gene

  8. TREATMENT HISTORY Imatinib n=31 12/31: post IFN 19/31: frontline Nilotinib n=2 2/2 frontline Switch n=31 23/31: intolerance 8/31: resistance/suboptimal response Dasatinib n=19 Nilotinib n=12 Switch n=3 2/3: intolerance 1/3: resistance/suboptimal response No switch n=28 Dasatinib n=17 Nilotinib n=11 Dasatinib n=1 Nilotinib n=2 STOP 2G-TKI

  9. 100 80 60 Survival without loss of MMR % 40 20 0 0 6 12 18 24 30 Months since 2G-TKI cessation STABLE MMR BY 6 MONTHS • Following 2G-TKI cessation, 8 pts lost MMR after a median time off-therapy of 2 months (2-5) Kaplan-Meier estimate of stable MMR after 2G-TKI cessation 6 month: 72.8% (95% CI: 55.4-90.1)

  10. PATTERNS OF BCR-ABL IN PATIENTS REMAINING OFF-THERAPY • 25/33 pts are currently off-therapy (median 6, range: 0-25) • 15/25 pts have a follow-up of at least 6 months (median 13, range: 6-25) 3 different patterns of molecular residual disease: Persistently detectable BCR-ABL n=1 Sustained undetectable BCR-ABL n=3 Occasionally detectable BCR-ABL Below the MMR threshold n=11

  11. Abstract #112

  12. Molecular and Cytogenetic Response at 3 MonthsofImatinibPredicts Progression-freeSurvival (PFS) and Overall Survival (OS) – a Follow-Up Analysis oftheRandomized CML-Study IV Abstract #783 Benjamin Hanfstein, MD, Martin C. Müller, MD, Philipp Erben, MD, Michael Lauseker, Susanne Saussele, MD, Ulrike Proetel, MD, Susanne Schnittger, PhD, Claudia Haferlach, MD, Hans-Jochem Kolb, MD, Stefan W. Krause, MD, ChristophNerl, MD, Dominik Heim, MD, Gabriela M. Baerlocher, MD, Jörg E. A. Schubert, MD, Hermann Einsele, MD, Mathias Hänel, MD, JolantaDengler, MD, Christiane Falge, MD, LotharKanz, MD, Andreas Neubauer, MD, Michael Kneba, MD, Frank Stegelmann, MD, Michael Pfreundschuh, MD, Cornelius F. Waller, MD, Markus Pfirrmann, PhD, JörgHasford, MD, Wolf-Karsten Hofmann, MD, RüdigerHehlmann, MD, Andreas Hochhaus, MD, for The SAKK and for The German CML Study Group

  13. N = 1,223 (assigned by April 30, 2010) Median age 52 years (16-85), 39% female Median observation time 4.8 years Treatment: Imatinib 400 mg/d n = 335 (27%) Imatinib 400 mg/d + Interferon alpha n = 366 (30%) Imatinib + Cytarabine n = 149 (12%) Imatinib 800 mg/d n = 373 (30%) Patients and samples

  14. Progression-free Survival (PFS)BCR-ABL IS at 3 months ≤10% vs. >10% ≤10% >10% BCR-ABLIS n 5Y-PFS ≤10% 499 93% >10% 189 87% p-value 0.003

  15. Overall Survival (OS)BCR-ABLIS at 3 months ≤10% vs. >10%

  16. Abstract #452

  17. Abstract #455

  18. CML ASH Highlights: Summary (I) • Ponatinib, a 3rd generation Abl kinase inhibitor, has remarkable activity in high-level resistant Ph+ leukemia confirmed in phase II data, particularly T315I mutation bearing and multidrug resistant chronic phase CML • DCC-2036, an oral ABL switch pocket inhibitor, shows good tolerability and activity in high-level resistant Ph+ leukemia and a novel mechanism • Discontinuation of therapy in patients on second-generation (nilotinib / dasatinib) Abl kinase inhibitors after imatinib shows similar pattern of early relapse but may lead to a higher fraction of stable, intermittent trace MRD+ patients sustained off therapy; longer follow-up is needed

  19. CML ASH Highlights: Summary (II) Timing and utility of Abl kinase mutation testing is clarified and incudes initial AP/BC disease, suboptimal and failure responses, and molecular relapse that leads to loss of MMR Multiple reports, including the large German CML IV study, point towards 3mo molecular response- <10% or >10% Bcr-Abl levels- as predictive for outcome Nilotinib as primary therapy for CP CML shows superior cytogenetic and molecular response and protection from progression in longer follow-up (3y) Bosutinib, although challenged by early GI toxicity, shows improvement in molecular response and cumulative cytogenetic response over imatinib at 2y

  20. OHSU clinical trials in CML/MPN Imatinib/other TKI resistant: Nilotinib + LDE (smoothend inhibitor) Imatinib/other TKI resistant: Observational registry (OHSU) Newly diagnosed CML: Nilotinib FL->elimination of MRD strategy/discontinuation Newly diagnosed CML: Observational registry (SIMPLICITY) CMML: 5-Azacitadine MF with thrombocytopenia: ruxolitinib All patients: sequenome/other diagnostic research studies

  21. Thank you for your attention! Thank you to all the research and clinical staff Thank you to RNs Linda Chalmers and Bashi Ratterree Please do not hesitate to call for questions, clinical trial availability, collaboration, diagnostics: 503-494-0376 / maurom@ohsu.edu Center for Hematologic Malignancies is committed to lead in OHSU’s vision and mission of specialized/personalized care for leukemia, lymphoma, myeloma..