1) Early molecular response at 3 months is an important predictor of long-term outcomes for CML patients on TKI therapy. Failure to achieve BCR-ABL ≤10% at 3 months is associated with higher risk of disease progression or death.
2) Achieving deeper levels of response such as MMR and MR4.5 is associated with improved progression-free and overall survival compared to lesser responses. TKIs like nilotinib and dasatinib have shown higher rates of deep molecular response compared to imatinib.
3) Avoiding progression to advanced phases such as accelerated or blast crisis is critical for long-term survival, as outcomes are much poorer once CML progresses beyond chronic phase
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...
Chronic myeloid leukemia
1. Update on Current Monitoring
Recommendations in CML
Far Eastern Memorial Hospital
New Taipei City, Taiwan
Hsieh Pei-Ying
2.
3. European Leukemia Net 2013:
Definitions of Response to TKIs first-line in 2013
References:
1. Baccarani M, et al. Presented at the 4th international Congress on Leukemia Lymphoma Myeloma. Istanbul, Turkey. May 22-25 2013.
Time Optimal Warning Failure
Diagnosis -
High risk
CCA in Ph+
-
3 months
PCgR
And/or < 10%
Minor CgR to 95%
Ph+
and/or > 10%
No CHR
and/or 95% Ph+
6 months
CCyR
And/or < 1%
< CCgR to minor
CgR
and/or > 1 – 10%
< minor CgR
and/or > 10%
12 months MMR
> 0.1 – 1%
(CCyR, no MMR)
> 1% Ph+
and/or > 1%
(No CCyR)
4. ENESTnd: Comparison of Nilotinib and
Imatinib in Newly Diagnosed CP CML
• Primary endpoint: MMR at 12 mos
• Secondary endpoint: durable MMR at 24 mos
Patients
diagnosed with
Ph+ CP CML
within 6 mos
(N = 846)
Nilotinib 300 mg BID
(n = 282)
Imatinib 400 mg QD
(n = 283)
Nilotinib 400 mg BID
(n = 281)
5-yr follow-up
Saglio G, et al. N Engl J Med. 2010;362:2251-2259. Larson RA, et al. Leukemia. 2012;26:2197-2203. Saglio G, et al.
ASH 2013. Abstract 92.
Stratified by Sokal risk
Extended to 10
yrs after
protocol
amendment
5. Patients newly
diagnosed with
CP CML
(N = 519)
Dasatinib 100 mg QD
(n = 259)
Imatinib 400 mg QD
(n = 260)
DASISION: Comparison of Dasatinib and
Imatinib in Newly Diagnosed CP CML
• Primary endpoint: confirmed CCyR at 12 mos
• Key secondary endpoints: MMR, time in confirmed
CCyR, time to confirmed CCyR and MMR, PFS, OS
Long-term
follow-up
Stratified by Hasford risk score
Jabbour E, et al. Blood. 2013;[E-pub ahead of print]. Cortes JE, et al. ASH 2013. Abstract 653.
11. CML Survival After Allo-SCT:
Stage Is a Key Issue
*Includes both matched related and unrelated donors.
Pts receiving allo-SCT at FHCRC from 1995 to present. Figure is courtesy of Dr. Ted Gooley.
1.0
0.8
0.6
0.4
0.2
0
ProbabilityofSurvival
0 2 4 6 8 10 12 14 16
Yrs After Transplantation
CP (n = 576)
AP (n = 125)
BP/remission (n = 62)
BP (n = 44)
CP
AP
BP
11
12. Progression to AP/BC in ENESTnd Study
• Rates of progression to AP/BC were lower with nilotinib vs imatinib when including all
progressions occurring on study
• 2 new cases of progression to AP/BC after discontinuation of core treatment were observed
between the 4-yr analysis and the current analysis
• 1 in the imatinib arm and 1 in the nilotinib 300 mg BID arm
• BCR-ABL > 10%IS at 3 mos for both patients
Imatinib 400 mg BID
(n = 283)
Nilotinib 300 mg BID
(n = 282)
Nilotinib 400 mg BID
(n = 281)
Saglio G, et al. ASH 2013. Abstract 92.
Patients(n)
Progressions of Study
7.1% 3.5% 2.1%
P = .0588
P = .0047
25
20
15
10
5
0
20
10
6
New events in Yr 5
13. Progression to AP/BC in DASISION Study
n =
Patients(n)
On Study Including Follow-up Beyond
Discontinuation (ITT)*
14 (5.4%)
8(3.1%)
12
18
Dasatinib 100 mg QD Imatinib 400 mg QD
259 260 259 260
0
5
20
10
15
Cortes JE, et al. ASH 2013. Abstract 653.
15. PFS (to AP/BP) for CCyR with/without
MMR@18m in IRIS trial 5 yrs F/U
Druker et al, N Engl J Med 2006;355:2408-17.
P<0.001 for whole group
P=0.11 for CCyR
with/without MMR
15
17. CCyR with various MR@18m
• 差異無法反應在Transformation-free survival or OS
Falchi elt al, Am. J. Hematol. 88:1024–1029, 2013
Transformation-free survival Overall survival
17
22. a Includes events occurring on core or extension treatment or during follow-up after treatment discontinuation.
b Patients for whom the principle cause of death was either “study indication” or “unknown” or not reported but occurred subsequent to a
documented progression to AP/BC.
Imatinib
400 mg QD
(n = 283)
Nilotinib
300 mg BID
(n = 282)
Nilotinib
400 mg BID
(n = 281)
Estimated 5-year PFS, % 91.1 92.0 95.3
Progressions and deaths, n 23 22 11
Hazard ratio (95% CI) — 0.92 (0.51-1.65) 0.46 (0.23-0.95)
P value .77 .03
Estimated 5-year OS, % 91.6 93.6 96.0
Total deaths, n 21 18 10
Deaths in patients with advanced
CML, nb 15 6 4
Hazard ratio (95% CI) — 0.84 (0.45-1.58) 0.46 (0.22-0.98)
P value — .58 .04
There were 6 newly reported deaths in year 5
Imatinib (n = 2): both due to study indication
Nilotinib 300 mg BID (n = 3): study indication, rectal cancer, and pneumonia
Nilotinib 400 mg BID (n = 1): sepsis
22 Saglio G, et al. Blood. 2013:[abstract 92].
PFS and OS in ENESTnd (5-year)
26. STIM Study: Stop IMatinib
N=100
STOPSustained CMR
for ≥ 2 years
Start
Imatinib
CMR
Q- RT-PCR from peripheral blood
every month in the first year and
every 2 months thereafter
Five BCR–ABL analyses by
Q- RT-PCR during these 2
years
Sixth datapoint checked
in centralized laboratory
Mahon FX et al. The Lancet Oncology, 2010;11(11): 1029-1035.
Molecular recurrence: positivity of
BCR–ABL transcript in Q-RT-PCR
confirmed by a second analysis point
indicating the increase of one log in
relation to the first analysis point, at
two successive assessments, or loss
of MMR at one point.
27. Treatment-free Survival of the STIM Study
Median follow up: 55 months (range 9-72)
Mahon et al., ASH 2013 [abstract 255]
36. Ultradeep Sequencing of TKI-Resistant BCR-
ABL Mutations
• Low-level resistance mutations identified in patients who develop resistance
to second-generation TKIs following previous TKI failure
Soverini S, et al. ASH 2013. Abstract 380.
Sanger sequencing
Ultradeep sequencing
F317L
E255V
Y253H
T3151 T3151 T3151T3151 T3151
F317L
T3151
V299L
Y253H
Patient
Mutations(n) CP AP myBC lyBC Ph+ ALL
6
5
4
3
2
1
0
37. PACE Trial of Ponatinib in TKI-Resistant CML:
2-Yr Update
• Ponatinib: oral BCR-ABL TKI
• Active against multiple mutations including T315I
• Heavily pretreated study population
• CP CML pts: ≥ 2 TKIs: 93%; ≥ 3 TKIs: 60%
• Current follow-up: 2 yrs
Cortes JE, et al. ASH 2013. Abstract 650.
Pts with CML or Ph+ ALL
resistant or intolerant to
dasatinib or nilotinib or with
emergent T315I mutation
(N = 449)
Ponatinib 45 mg/day
38. PACE: Response in Heavily Pretreated Pts
With Ph+ Leukemias
• Estimated 89% of pts with CP CML to maintain MCyR ≥ 2 yrs
• Estimated 21% of pts with AP CML to maintain MaHR ≥ 2 yrs
Outcome CP CML AP CML BP CML Ph+ ALL
MCyR* CCyR* MMR* MaHR† MaHR MaHR
R/I, % 56 48 31 62 32 50
T315I, % 72 70 58 61 29 36
Total, % 60 54 38 61 31 41
Median TTR, mos 2.8 2.9 5.5 0.7 1.0 0.7
*At any time after initial ponatinib dose.
†14 AP CML pts with baseline MaHR and 1 AP CML pt with no baseline MaHR assessment counted as
nonresponders.
39. Most Common AEs With Ponatinib
*Combines the terms erythematous, macular, and papular rash.
Select Any Grade
AEs, %
CP CML (n = 270) Total Population (N = 449)
Any Grade Grade 3/4 Any Grade Grade 3/4
Nonhematologic
Rash* 44 4 40 4
Abdominal pain 43 9 40 9
Headache 41 3 36 2
Dry skin 41 3 36 2
Hypertension 27 10 24 9
Elevated lipase 25 12 21 12
Hematologic
Thrombocytopenia 44 35 43 35
Neutropenia 19 16 25 22
Anemia 16 9 22 15
41. Most Common Vascular AEs With Ponatinib
AE, %
US Ponatinib Insert
(7/23/2012)
Median Follow-up: 12 Mos
(340 Pt-Yrs)
PACE Trial (9/3/2013)
Median Follow-up: 24 Mos
(578 Pt-Yrs)
Serious AE AE Serious AE AE
Cardiovascular 5 6 6 9
Cerebrovascular 2 3 4 6
Peripheral vascular 2 4 4 6
Venous
thromboembolism
2 3 3 5
Total vascular
occlusion
By FDA criteria 9 14 14 20
By trial criteria 10 18 15 24
42. Conclusion
• 2nd generation TKIs can provide faster and deeper response in CML,
CP; and a trend to better OS.
• 2nd generation TKIs provide higher rate of fitting new ELN guideline.
• 40% of patients with a durable CMR on imatinib therapy.
• Monitor the risk factors of arterial events is important when you
chose 2nd generation TKIs.
Editor's Notes
BID, twice daily; CML, chronic myeloid leukemia; CP, chronic phase; MMR, major molecular response; Ph, Philadelphia chromosome; QD, once daily.
SCT, stem cell transplantation
We have clearly—historically and currently—seen that survival after transplant is definitely phase-dependent, with patients with chronic phase doing very well still, although our data, unfortunately, has been diluted by all of our high-risk patients, which we are now transplanting in 2001 and forward after the TKIs were approved. But, we always have seen—and continue to see—the lower proportions of surviving patients with accelerated and blast crisis. So, one of our most important messages in CML is to not allow a patient to progress in order to get them to transplant. We need to identify them before they progress.
Panel B shows that at 60 months, of the 139 pa-
tients with a complete cytogenetic response and a reduction in levels of
BCR-ABL transcripts of at least 3 log, 100% were free from progression to
the accelerated phase or blast crisis. The corresponding rate for 54 patients
with a complete cytogenetic response and a reduction in levels of BCR-ABL
transcripts of less than 3 log was 98%; the rate for 88 patients without a
complete cytogenetic response was 87% (P<0.001; P = 0.11 for the compari-
son between patients with a major molecular response and those without
a major molecular response). At 18 months, 86 patients had discontinued
imatinib and 186 patients had achieved a complete cytogenetic response
but did not have a PCR result available.
Landmark analysis at 18 and 24 months for transformation-free survival (A and B) and overall survival (C and D) according to different levels of molecular
response in patients with complete cytogenetic response. P values for the comparison MR4.5, MR4, MMR, and no-MR versus UND are 0.03, 0.25, 0.37, and 0.15,
respectively (A), 0.16, 0.30, 0.61, and 0.16, respectively (B), 0.48, 0.86, 0.89, and 0.24, respectively (C), and 0.94, 0.99, 0.38, and 0.44, respectively (D). [Color figure
can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
BID, twice daily; CML, chronic myeloid leukemia; CP, chronic phase; MMR, major molecular response (BCR-ABL ≤ 0.1%); QD, once daily.
BID, twice daily; MR4.5, molecular response of 4.5 log reduction (BCR-ABL ≤ 0.0032%); QD, once daily.
5 extra-hematological deaths were observed: 1 case in DMR after 9 months of imatinib cessation (due to myocardial infarction) and 4 cases in the molecular relapse group due to stroke, mesothelioma, and gastric carcinoma respectively).
ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; CP, chronic phase; Ph, Philadelphia chromosome; TKI, tyrosine kinase inhibitor.
ALL, acute lymphoblastic leukemia; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; MaHR, major hematologic response; MCyR, major cytogenetic response; Ph, Philadelphia chromosome; R/I, resistance or intolerance to dasatinib and/or nilotinib; TTR, time to relapse.