Transcript OHSU Updates in Hematology and Breast Cancer Conference CML ASH Update Michael J. Mauro, MD.

OHSU Updates in Hematology
and
Breast Cancer Conference
CML ASH Update
Michael J. Mauro, MD
CML Abstracts
Novel Agents
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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
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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
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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
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Abstract # 112: Validation of the New ELN Recommendations for BCR-ABL KD Mutation Analysis in
CML: an Analysis of the CML GIMEMA WP Studies
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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
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Abstract # 452: Nilotinib versus Imatinib in Patients with Newly Diagnosed Philadelphia ChromosomePositive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 3-Year Follow-Up
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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)
Abstract #604
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 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
DESIGN AND ENDPOINTS
D1
Undetectable
BCR-ABL
≥ 24 months
M6
M12
M18
STOP
2G-TKI
Monthly
RQ-PCR
RQ-PCR
every 2-3 months
• 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
M24
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 (BCRABL/ABL ratio > 0.1% IS)
* Undetectable BCR-ABL at local laboratories with at least 20 000x2 copies of the ABL1 control gene
TREATMENT HISTORY
Imatinib
n=31
Nilotinib
n=2
12/31: post IFN
19/31: frontline
2/2 frontline
Switch n=31
23/31: intolerance
8/31: resistance/suboptimal response
Dasatinib n=19
Nilotinib n=12
No switch n=28
Dasatinib n=17
Nilotinib n=11
Switch n=3
2/3: intolerance
1/3: resistance/suboptimal response
Dasatinib n=1
Nilotinib n=2
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)
Survival without loss of MMR %
Kaplan-Meier estimate of stable MMR after 2G-TKI cessation
6 month: 72.8% (95% CI: 55.4-90.1)
100
80
60
40
20
0
0
6
12
18
24
Months since 2G-TKI cessation
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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-ABL
n=3
Persistently detectable BCR-ABL
n=1
Occasionally detectable BCR-ABL
Below 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 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, 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
Patients and samples
 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%)
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
Overall Survival (OS)
BCR-ABLIS at 3 months ≤10% vs. >10%
≤10%
>10%
BCR-ABLIS
n
5Y-OS
≤10%
501
95%
>10%
191
87%
p-value
<0.001
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 / [email protected]
• 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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