OHSU Updates in Hematologyand

Breast Cancer Conference

CML ASH Update

Michael J. Mauro, MD

CML AbstractsNovel 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 Months of Imatinib Predicts Progression-free Survival (PFS) and Overall Survival (OS) – a Follow-Up Analysis of the Randomized 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

Abstract #109

Abstract #601

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

Selected by the ASH Program Session Name: 632. Chronic Myeloid Leukemia - Therapy: New Drugs, New ProceduresSession 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

Abstract #604

DESIGN AND ENDPOINTS

• 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

M6 M12 M18 M24D1

STOP2G-TKI

MonthlyRQ-PCR

RQ-PCRevery 2-3 months

UndetectableBCR-ABL

≥ 24 months

TRIAL DETAILS:

ELIGIBILITY• 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

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)

* Undetectable BCR-ABL at local laboratories with at least 20 000x2 copies of the ABL1 control gene

TREATMENT HISTORY

Imatinibn=31

12/31: post IFN19/31: frontline

Nilotinibn=2

2/2 frontline

Dasatinib n=19Nilotinib n=12

Dasatinib n=1Nilotinib n=2

Switch n=3123/31: intolerance8/31: resistance/suboptimal response

Switch n=32/3: intolerance1/3: resistance/suboptimal response

Dasatinib n=17Nilotinib n=11

No switch n=28

STOP 2G-TKI

STABLE MMR BY 6 MONTHS

• Following 2G-TKI cessation, 8 pts lost MMR after a median time off-therapy of 2 months (2-5)

6 month: 72.8% (95% CI: 55.4-90.1)

Kaplan-Meier estimate of stable MMR after 2G-TKI cessation

0

20

40

60

80

100

0 6 12 18 24 30

Months since 2G-TKI cessation

Su

rviv

al

wit

ho

ut

los

s o

f M

MR

%

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:

Sustained undetectable BCR-ABLn=3

Persistently detectable BCR-ABLn=1

Occasionally detectable BCR-ABLBelow the MMR threshold

n=11

Abstract #112

Factor Analyzed N N positive for KD

mutation (%)

De novo CP CML 58 1 (2%)

De novo AP/BC CML 12 2 (17%)

IM Failure (ELN criteria) 166 45 (27%)

Suboptimal IM Response (ELN) 233 11 (5%)

Rise in PCR without loss of MMR 70 0 (0%)

Rise in PCR with loss of MMR 89 4 (5%)

NIL/DAS ‘Failure’ (ELN criteria) 19 11 (58%)

NIL/DAS ‘Suboptimal’ (ELN criteria) 19 4 (21%)

Molecular and Cytogenetic Response at 3 Months

of Imatinib Predicts Progression-free Survival

(PFS) and Overall Survival (OS) – a Follow-Up

Analysis of the Randomized CML-Study IVAbstract #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, Christoph Nerl, MD, Dominik Heim, MD, Gabriela M.

Baerlocher, MD, Jörg E. A. Schubert, MD, Hermann Einsele, MD, Mathias Hänel, MD, Jolanta

Dengler, MD, Christiane Falge, MD, Lothar Kanz, MD, Andreas Neubauer, MD, Michael Kneba,

MD, Frank Stegelmann, MD, Michael Pfreundschuh, MD, Cornelius F. Waller, MD, Markus

Pfirrmann, PhD, Jörg Hasford, MD, Wolf-Karsten Hofmann, MD, Rüdiger Hehlmann, MD,

Andreas Hochhaus, MD, for The SAKK and for The German CML Study Group

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 + Cytarabinen = 149 (12%)

Imatinib 800 mg/dn = 373 (30%)

Patients and samples

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%0.003

p-value

BCR-ABLIS n 5Y-OS

≤10% 501 95%

>10% 191 87%<0.001

p-value

>10%

≤10%

Overall Survival (OS)

BCR-ABLIS at 3 months ≤10% vs. >10%

Abstract #452

Abstract #455

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

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

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

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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..

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