1) The document discusses response rates and outcomes for patients with chronic myeloid leukemia (CML) treated with various tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, nilotinib, and bosutinib.
2) It reports that achieving a major cytogenetic response or deeper molecular response (e.g. MMR) at certain timepoints (e.g. 12 months) on imatinib is associated with improved progression-free and overall survival.
3) For patients who become resistant or intolerant to imatinib, the second-generation TKIs dasatinib, nilotinib and bosutinib have response rates ranging from
Challenges and Considerations in Clinical Development of "Targeted Therapies"...Medpace
In this webinar, Medpace experts discuss key clinical, operational and laboratory considerations, lessons-learned, and best practices for accelerating the global development of safe and effective targeted therapeutics, using acute myeloid leukemia (AML) to highlight the complexities.
ADC’s - What Everyone with MBC Should Know about Antibody Drug Conjugatesbkling
Antibody drug conjugates (ADC’s), a novel class of anticancer agents, have been around for decades but recently great strides have been made in metastatic breast cancer. Next generation ADC’s, sometimes referred to as ' Trojan Horses' have shown promising efficacy in all subtypes of MBC. Join Dr. Erika Hamilton, Director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, and partner with Tennessee Oncology PLCC, as she presents an overview of ADC’s, biomarkers and clinical mapping, current treatment options, as well as the promising trials to keep an eye on. There will be time for your questions throughout the presentation.
chimeric antigen receptor, its structure and role in killing tumor cells,mechanism of antitumor killing, car's in clinic,evolution of cars and new chimeric antigen models
Challenges and Considerations in Clinical Development of "Targeted Therapies"...Medpace
In this webinar, Medpace experts discuss key clinical, operational and laboratory considerations, lessons-learned, and best practices for accelerating the global development of safe and effective targeted therapeutics, using acute myeloid leukemia (AML) to highlight the complexities.
ADC’s - What Everyone with MBC Should Know about Antibody Drug Conjugatesbkling
Antibody drug conjugates (ADC’s), a novel class of anticancer agents, have been around for decades but recently great strides have been made in metastatic breast cancer. Next generation ADC’s, sometimes referred to as ' Trojan Horses' have shown promising efficacy in all subtypes of MBC. Join Dr. Erika Hamilton, Director of Breast Cancer and Gynecologic Cancer Research at Sarah Cannon Research Institute, and partner with Tennessee Oncology PLCC, as she presents an overview of ADC’s, biomarkers and clinical mapping, current treatment options, as well as the promising trials to keep an eye on. There will be time for your questions throughout the presentation.
chimeric antigen receptor, its structure and role in killing tumor cells,mechanism of antitumor killing, car's in clinic,evolution of cars and new chimeric antigen models
Audio and slides for this presentation are available on YouTube: http://youtu.be/ozNSEND5PbE
Erica Mayer, MD, MPH, of the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, discusses triple-negative breast cancer and what makes it different from other forms of breast cancer. Mayer also talks about treatment options for triple-negative breast cancer and what you need to know about clinical trials for the disease.
T cells genetically engineered to express chimeric antigen receptors (CAR) have proven an impressive therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. Key challenges relating to CAR T cells include the lack of tumor exclusive target, restricted CAR-T cell trafficking to tumor sites, antigen escape and heterogeneity as well as a highly immunosuppressive microenvironment. In this report, we review the current state of the CAR-T technologies as a clinical treatment in solid tumor and we highlight the preclinical innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with solid malignancies.
Justin F. Gainor, MD; Kurt Schalper, MD, PhD; and Edward B. Garon, MD, MS prepared useful Practice Aids pertaining to immunotherapy for this CME/MOC/CC/CNE activity titled, "New Frontiers in Precision Immuno-Oncology: Leveraging Biomarkers to Refine and Expand the Use of Cancer Immunotherapies and Combinations." For the full presentation, monograph, complete CME/MOC/CC/CNE information, and to apply for credit, please visit us at http://bit.ly/2UJuQBq. CME/MOC/CC/CNE credit will be available until April 25, 2020.
Optimizing Treatment Sequencing for Patients With Relapsed/ Refractory Multi...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Shaji Kumar, MD, Professor of Hematological Malignancies
Mayo Clinic Cancer Center, offers expert insight on the assessment of MM, emerging and current therapies, cutting edge approaches to personalized treatments plans, and much more.
Final presentation for BIOL405, NSC, Spring 2014. Presented by Kevin Hugins and Duy-Khiem Chanh Pham. This presentation addressed the use of Chimeric Antigen Receptors for gene therapy for cancer. Gene therapy was first conceptualized to alter debilitating fates of genetic diseases. Gene therapy technology can help introduce new functional DNA to replace mutated genes. The idea first arose in 1972 when Friedmann and Roblin authored a paper, “Gene therapy for human genetic disease?”, demonstrating that exogenous DNA can be taken up by mammalian cells (1). They proposed that the same procedure could be done on humans to correct genetic defects by introducing therapeutic DNA. Currently, genetic modification of T lymphocytes has been the major area of research for treating malignant tumors. This technique seeks to create chimeric antigen receptor (CAR) in T cells by genetically modifying them in vitro and reintroduce them back into blood circulation. The T cells are unique to every patient and the chimeric antigen receptors are unique to the tumor that it is targeting.
Audio and slides for this presentation are available on YouTube: http://youtu.be/ozNSEND5PbE
Erica Mayer, MD, MPH, of the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, discusses triple-negative breast cancer and what makes it different from other forms of breast cancer. Mayer also talks about treatment options for triple-negative breast cancer and what you need to know about clinical trials for the disease.
T cells genetically engineered to express chimeric antigen receptors (CAR) have proven an impressive therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. Key challenges relating to CAR T cells include the lack of tumor exclusive target, restricted CAR-T cell trafficking to tumor sites, antigen escape and heterogeneity as well as a highly immunosuppressive microenvironment. In this report, we review the current state of the CAR-T technologies as a clinical treatment in solid tumor and we highlight the preclinical innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with solid malignancies.
Justin F. Gainor, MD; Kurt Schalper, MD, PhD; and Edward B. Garon, MD, MS prepared useful Practice Aids pertaining to immunotherapy for this CME/MOC/CC/CNE activity titled, "New Frontiers in Precision Immuno-Oncology: Leveraging Biomarkers to Refine and Expand the Use of Cancer Immunotherapies and Combinations." For the full presentation, monograph, complete CME/MOC/CC/CNE information, and to apply for credit, please visit us at http://bit.ly/2UJuQBq. CME/MOC/CC/CNE credit will be available until April 25, 2020.
Optimizing Treatment Sequencing for Patients With Relapsed/ Refractory Multi...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Shaji Kumar, MD, Professor of Hematological Malignancies
Mayo Clinic Cancer Center, offers expert insight on the assessment of MM, emerging and current therapies, cutting edge approaches to personalized treatments plans, and much more.
Final presentation for BIOL405, NSC, Spring 2014. Presented by Kevin Hugins and Duy-Khiem Chanh Pham. This presentation addressed the use of Chimeric Antigen Receptors for gene therapy for cancer. Gene therapy was first conceptualized to alter debilitating fates of genetic diseases. Gene therapy technology can help introduce new functional DNA to replace mutated genes. The idea first arose in 1972 when Friedmann and Roblin authored a paper, “Gene therapy for human genetic disease?”, demonstrating that exogenous DNA can be taken up by mammalian cells (1). They proposed that the same procedure could be done on humans to correct genetic defects by introducing therapeutic DNA. Currently, genetic modification of T lymphocytes has been the major area of research for treating malignant tumors. This technique seeks to create chimeric antigen receptor (CAR) in T cells by genetically modifying them in vitro and reintroduce them back into blood circulation. The T cells are unique to every patient and the chimeric antigen receptors are unique to the tumor that it is targeting.
Roundtable Expert Discussions on CML Clinical Debates: A Collaborative Video Viewpoint Series With Medscape
This video viewpoint in its original and unaltered format is for educational purposes and is current as of May 31, 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at the user’s own risk, and all users should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
All u want to knew about epidemiology, pathology, pathogenesis, clinical picture, investigation, differential diagnosis, different treatment modalities.
Best of ASCO Metastatic Non-Small Cell Lung CancerH. Jack West
Dr. Jack West's presentation on highlights in advanced non-small cell lung cancer from ASCO 2014, focusing on new agents ramucirumab and necitumumab for broad NSCLC populations, crizotinib and ceritinib for ALK-positive NSCLC, EGFR inhibitor-options of afatinib and bevacizumab added to erlotinib for first line treatment of EGFR mutation-positive NSCLC, and AZD9291 or CO1686 for EGFR mutation-positive patients with acquired resistance.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
http://sandymillin.wordpress.com/iateflwebinar2024
Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
Francesca Gottschalk - How can education support child empowerment.pptxEduSkills OECD
Francesca Gottschalk from the OECD’s Centre for Educational Research and Innovation presents at the Ask an Expert Webinar: How can education support child empowerment?
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
Acetabularia Information For Class 9 .docxvaibhavrinwa19
Acetabularia acetabulum is a single-celled green alga that in its vegetative state is morphologically differentiated into a basal rhizoid and an axially elongated stalk, which bears whorls of branching hairs. The single diploid nucleus resides in the rhizoid.
Honest Reviews of Tim Han LMA Course Program.pptxtimhan337
Personal development courses are widely available today, with each one promising life-changing outcomes. Tim Han’s Life Mastery Achievers (LMA) Course has drawn a lot of interest. In addition to offering my frank assessment of Success Insider’s LMA Course, this piece examines the course’s effects via a variety of Tim Han LMA course reviews and Success Insider comments.
Home assignment II on Spectroscopy 2024 Answers.pdf
IMATINIB RESISTANT CML
1. Elias Jabbour, MD
University of Texas – M. D. Anderson
Cancer Center
CML and Imatinib Resistance:
Which TKI and When?
2. CML and Imatinib Resistance:
Which TKI and When?
Marcos de Lima, MD
Stem Cell Transplantation Program
Case Western Reserve University
University Hospitals Seidman Cancer Center
Cleveland - OH
3. Results with Imatinib in Early CP
CML – The IRIS Trial at 8-Years
• 304 (55%) patients on imatinib on study
• Projected results at 8 years:
–CCyR 83%
• 82 (18%) lost CCyR, 15 (3%) progressed to
AP/BP
–Event-free survival 81%
–Transformation-free survival 92%
• If MMR at 12 mo: 100%
–Survival 85% (93% CML-related)
• Annual rate of transformation: 1.5%, 2.8%,
1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4%
Deininger et al; Blood 2009; 114: Abst# 1126
5. 5
IRIS. Survival Without AP/BC Worse If No
Major CG Response at 12 mos
Estimated rate at 60 months
n= 86 93%
n= 73 81%
n= 350 97%
} p<0.001} p=0.20CCyR
PCyR
No MCyR
Response at 12 months
%withoutAP/BC
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
M o n th s s in c e r a n d o m iz a tio n
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6
Rx aim: major CG response (Ph ≤ 35%)
6. Criteria for Failure and Suboptimal
Response to Imatinib
Time
(mo)
Response
Failure Suboptimal Optimal
3 No CHR No CG
Response < 65% Ph+
6 No CHR
>95% Ph+ ≥35% Ph+ ≤35% Ph+
12 ≥35% Ph+ 1-35% Ph+ 0% Ph+
18 ≥5% Ph+ No MMR MMR
Any
Loss of CHR
Loss of CCgR
Mutation
CE
Loss of MMR
Mutation
Stable or
improving
MMR
Baccarani. JCO 2009; 27: 6041-51
7. NCCN Treatment Recommendations
3-Month Follow-up Therapy
BCR-ABL
transcript levels
≤10% by QPCR
International
Scale (IS)
or
PCyR on bone
marrow
cytogenetics
BCR-ABL
transcript
levels >10% by
QPCR using the
IS
or
<PCyR on bone
marrow
cytogenetics
Continue
same dose
of IM,
DAS, or
NIL
• Evaluate patient
compliance and
drug-drug
interactions
• Mutational
analysis
Monitor
with
QPCR
every
3 mo
DAS 100 mg daily
NIL 400 mg BID
Evaluation and
discussion of HSCT
Clinical trial
3-mo
evaluation
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous
leukemia. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Revised September 13, 2012.
No
relapse
Relapse
8. Adherence Is the Most Important Factor
Contributing to Molecular Responses
Marin D et al. J Clin Oncol. 2010;28(14):2381-2388.
Adherence monitored over a period of 3 months using a microelectronic
monitoring device in the imatinib bottle cap. Patients were not aware of the
device.
0.1
12
Time Since Start of Imatinib Therapy (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0 6 18 24 30 36 42 48 54 60 66 72
ProbabilityofMMR Adherence >90% (n = 64)
Adherence ≤90% (n = 23)
P<0.001
10. MDACC Retrospective Analysis:
MCyR at 6 Months Associated With OS
Patients with MCyR have better OS than patients that do not
Landmark analysis at 6 mos
0 12 24 36 48 60 72
Cytogenetic response at 6 mos Total Dead P-value
Complete 201 5
Partial 39 1
Minor 10 3
Othersa
9 3
0.85
0.01
0.62
1.0
0.8
0.6
0.4
0.2
0
Proportionalive
Months
Kantarjian H. Cancer. 2008;112:837–845.
11. MDACC Retrospective Analysis:
CCyR at 12 Months Associated With PFS
Patients with CCyR have better PFS than patients that do not.
Similar results were observed in patients achieving CCyR at 18 and 24 mos.
Landmark analysis at 12 mos
ProportionPFS
1.0
0.8
0.6
0.4
0.2
0
0 12 24 36 48 60 72
Months
Cytogenetic
response at
12 mos Total Failure P-value
Complete 214 7
Partial 19 3
Minor 5 2
Others 8 5
0.02
0.2
0.22
Kantarjian H. Cancer. 2008;112:837–845.
12. EFS and Survival by 12-month Response-CCyR
with vs without MMR with TKI Frontline Rx
Jabbour E et al. Blood. 2011.
13. Outcome by 12-Month Response
in CML CP
•848 pts randomized to IM 400mg, IM 800mg,
or IM 400 + IFN
•Median FU: 40 months
12-month
BCR-ABL/ABL (IS)
N
Percentage
PFS OS
<0.1% 341 99 99
0.1-1% 240 97 98
>1% 267 94 93
P value 0.0023 0.0011
•Outcome independent of treatment arm
Hehlman et al. JCO 2011;29:1634-42
CCyR
14. Probabilityofsurvival
Time from onset of imatinib therapy (years)
BCR-ABL/ABL<9.8% OS= 93.3%
BCR-ABL/ABL>9.8% OS= 54%
p<0.0001
Survival After Imatinib Therapy by
Molecular Response Achieved at 3
Months
Marin et al, JCO 2011; [Epub ahead of print
• Optimal PCR value determined by Receiver operating
characteristic (ROC) curve
15. CML IV: Long-Term Impact of
Response at 3 Months
•1223 pts randomized to imatinib 400, imatinib +
IFN, imatinib + ara-C, imatinib 800
•3 month analysis: PCR in 692 pts, cytogenetics in
460
•3 mo transcript levels predictive of achievement
of CCyR and MMR
% 5-year
outcome
Cytogenetics
(% Ph+)
Molecular
[BCR-ABL/ABL (IS)]
≤35% >35% ≤10% >10%
PFS 94 87 93 87
OS 95 87 95 87
Hanfstein et al. ASH 2011; Abstract #783
16. OS by Response to TKI at 3
Months at MDACC
Naqvi et al. ASH 2011; Abstract #3784
17. EFS by Response to TKI at 3
Months at MDACC
Naqvi et al. ASH 2011; Abstract #3784
18. Failure On Imatinib And Strategies
Imatinib Failure ↑ Imatinib
Second
Generation
TKI
• Ph 100% at 6 mos _ +
• Ph ≥ 35% at 12
mos
+ +
• No CGCR in yr 2 + +
• CG relapse + +
• Hematologic
relapse
_
+
30. 2nd
-Generation TKI in CML CP
Post- Imatinib Failure
Toxicity Dasatinib Nilotinib Bosutinib
Anemia 13 11 13
Neutropenia 35 31 18
Thrombocytopenia 23 30 24
Shah et al. Haematologica 2010; 95: 232-40
Kantarjian et al. Blood 2011; 117: 1141-45
Cortes et al. Blood 2011; 118; 4567-76
31. Better Outcome on Dasatinib with
Earlier Intervention
• Patients on dasatinib studies analyzed by
failure status on imatinib: loss of MCyR vs
loss of CHR
• Status at IM Failure No.
Percentage
CCyR MMR
Loss of MCyR 151 72 60
Loss of CHR & MCyR 33 42 29
Loss of CHR (never MCyR) 109 26 26
Quintás-Cardama. Cancer 115: 2912-21, 2009
32. Dasatinib Early Intervention
EFS & OS
Quintás-Cardama. Cancer 115: 2912-21, 2009
Event-Free Survival Overall Survival
Time to intervene:
Loss of MCyR
33. Prognosis with 2nd
TKIs. Survival
•Adverse factors: PS ≥1 and lack of CyR to imatinib
Jabbour. Blood 117: 1822-7, 2011
34. No MCyR (27)
MCyR (59)
0
0.2
0.4
0.6
0.8
1
0 12 24 36
Months on second TKI
PFS(%)
PFS and Response to 2nd
TKI
Response @
12 mo
% AP/BP/Death/CHR
loss Next Year
MCyR 3%
No MCyR 17%
• 113 CML CP pts receiving nilotinib (n=43) or dasatinib
(n=70) after imatinib failure
Tam. Blood 112: 516-8, 2008
p = 0.003
35. Optimal Response to 2nd
TKIs. Survival
3-year survival (%)
Parameter Event-free Overall
CCyR by 3 months Yes 74 98
No 43 79
36. How Do You Choose The Second
Generation TKIs
• Disease characteristics
- AP/BP: favor dasatinib (?) and combinations
- chronic: see below
• Mutations
-T315I → none
- nilotinib IC50 > 150nM → avoid
- dasatinib IC50 > 3nM → avoid
• Patient Hx
- Hypertension, CHF, lung problems, COPD →
avoid dasatinib, consider bosutinib/nilotinib
- Severe diabetes, pancreatitis Hx,
atherosclerosis → avoid nilotinib, consider
bosutinib/dasatinib
- QTc problems → be cautious with all (?)
37. Ponatinib Phase 2 Study - PACE
Response Characteristics CP-CML
• 93% failed ≥2 TKI, 58% failed ≥3 TKI
Response Rate, n (%) N=267
Any Cytogenetic Response 180 (67)
MCyR 149 (56)
CCyR 124 (46)
MMR 91 (34)
MR4.5
39 (15)
BCR-ABL ≤10% at 3 months, n/N(%) 142/240 (59)
1 prior approved TKI 14/16 (88)
Median Time to Response*
, months [range]
MCyR 2.8 [1.6 – 11.3]
MMR 5.5 [1.8 – 19.2]
• 91% MCyR sustained at 12 months (K-M)
Cortes J, et al. Blood. 2012;120: Abstract 163.
38. Ponatinib Phase 2 Study - PACE
Response by Baseline Mutation CP-CML
Baseline Mutations in at Least 2 Patients (Excluding T315I)
P-Loop Non P-Loop
NumberofPatients
MCyR
CP-CML
N=267
n/N (%)
R/I, no
mutation 66/136 (49)
R/I, any
non-T315I
mutation
38/67 (57)
T315I
mutation 45/64 (70)
Cortes J, et al. Blood. 2012;120: Abstract 163.
39. Ponatinib Phase 2 Study - PACE
Response in Advanced Phase
n (%)
AP-CML
N=83
BP-CML N=62
Ph+ ALL
N=32Myeloid
N=52
Lymphoid
N=10
MaHR* 47 (57) 15 (29) 4 (40) 13 (41)
Any CyR** 46 (55) 19 (37) 5 (50) 15 (47)
MCyR 32 (39) 10 (19) 4 (40) 15 (47)
CCyR 20 (24) 8 (15) 3 (30) 12 (38)
MMR#
13 (16) N/A N/A N/A
*MaHR = primary endpoint; 14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR
assessment counted as non-responders
**CCyR + PCyR + minor CyR + minimal CyR
#
MMR was assessed on the International Scale using peripheral blood; Patients missing a valid baseline MMR
assessment , or who met the criteria for MMR at baseline, were counted as non-responders
Kantarjian HM, et al. Blood. 2012;120: Abstract 915.
40. Omacetaxine for CML CP After
Failure to ≥2 TKI
• 122 pts with CML CP (n=81) or AP (n=41) with ≥2
prior TKI
• Omacetaxine 1.25 mg/m2
BID x14d, then x7d
Response, % CP
N=81
AP
N=41
Primary endpoint MCyR 20% MaHR 27%
CCyR 10% CHR 24%
Median duration, mo 17.7 9
Median PFS, mo 9.6 4.7
Median OS, mo 33.9 16
• 11 pts (9 CP, 2 AP) ongoing response
• Median 35 cycles over median 39 months
• Median response duration: 14 mo CP, 24 mo AP
Kantarjian HM, et al. Blood. 2012;120: Abstract 2767.
41. Allo SCT. Second or Third Salvage?
• Imatinib failure in AP, BP: use new TKI as bridge to MRD, then
alloSCT ASAP
• T315I mutation in any CML phase: use AP 24534, other T315I
inhibitors, HHT, HU, others as bridge to MRD, then allo SCT
ASAP
• Imatinib failure in CP:
– if IC50 ↑, clonal evolution, or no major CG in 12 mos →
allo SCT (risk should also be reasonable: young, good
match)
– If not → TKI until failure
• Age ≥ 70 yrs or if poor match: may decide to forgo curative
allo SCT option for several years of CML control;
• Young patient (?)
• Financial considerations
42. Monitoring Patients with CML
While on TKI Therapy
• Adequate monitoring required to optimize
outcome / Not too much, not too little
• CCyR is associated with survival benefit
• MMR is associated with durable CCyR and may
therefore decrease probability of relapse
• CMR offers hope for treatment discontinuation
(clinical trials only)
• Results should be interpreted in the context of
alternative options
• Not failure criterion / QPCR ↑ in CCyR
Overall survival by MCyR vs no MCyR at 3 months p=0.156
Event free survival by MCyR vs No MCyR at 3 months p=0
Introducing dasatinib in patients with CML CP failing imatinib after loss of MCyR was associated with improved CCyR rates as well as EFS, PFS, and OS, compared with introducing dasatinib after loss of CHR or loss of CHR and CCyR, thus supporting the notion that switching therapy from imatinib to dasatinib early during the course of failure increases the chances of a favorable long-term outcome.
These 2 factors, older age and lack of any CG respose to previous imatinib therapy had similar effect on the EFS Patients with 0, 1, or 2 adverse factors had an estimated 18-month event-free survival with second generation TKI therapy of 81%, 54%, and 20%, respectively.
Achieving a major cytogenetic response is a known major determinant of outcome in previous generations of therapy including interferon alpha and imatinib. In a previous report from our institution, patients who achieved a major cytogenetic response after 12 months of therapy with second generation TKI had at least a better progression-free survival.
In the univariate analysis for event-free survival, factors associated with poor event-free survival were older age (> 55 years), lack of any cytogenetic response to previous imatinib therapy, an ECOG performance status ≥1 at the start of second generation TKI therapy, and more than ≥ 90% Philadelphia-positive metaphases at the start of second generation TKI therapy. Kinase domain sequencing was performed in only 88 patients. When added to the analysis, the presence of KD mutations with intermediate IC50 at the start of second generation TKI was associated with poor event-free survival. In the subsequent multivariate analysis, the lack of any cytogenetic response to previous imatinib therapy (p<0.001), and an ECOG performance status ≥1 at the start of second generation TKI therapy (p=0.007) were selected as independent factors associated with poor event-free survival.