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Optimal first-line treatment of chronic phase CML
순천향대학교병원
김 경 하
** Frontline approval of bosutinib on December 2017
Baccarni et al., Blood 2013;122:872-84. Courtesy of Dr DK Kim
Advances in CML treatment, particularly regarding TKI, mandate
regular updating of concepts and management
Response Criteria in CML
100%
10%
1%
0.1%
0.01%
0.001%
Diagnostic
1 log reduction
2 log reduction
3 log reduction
4 log reduction
5 log reduction
4.5 log reduction
~ MCyR (≤ 35% Ph+ in BM), 2nd line
~ CCyR (0% Ph+ in BM), Front line
MMR or MR3.0, Front line
MR4.0 (most reliable deep response)
MR5.0 or CMR
MR4.5, reliable parameter for CMR 0.0032%
International scale Log scale Definition of Response
• Imatinib
• Dasatinib
• Nilotinib
• Bosutinib
• Radotinib
Frontline treatment options
Selecting a frontline treatment
• Efficacy of TKI in first-line clinical trials
• Patient’s age
• Patient’s comorbidities
• TKI toxicity profile
• Adherence
• Risk score
• BCR-ABL transcript type
• Additional chromosomal abnormalities (ACAs)
Pro
bab
ility
of
surv
ival
Time from onset of imatinib therapy (years)
BCR-ABL/ABL<9.8% OS= 93.3%
BCR-ABL/ABL>9.8% OS= 56.9%
p<0.0001
Survival According to MR at 3 months: 282 Patients Treated with Imatinib 1st-line
Marin D, et al. J Clin Oncol 2012;30(3):232-8.
Individualized TKI selection - Efficacy
10%
CMR according to the BCR-ABL transcript level at 3 months
BCR-ABL/ABL≤0.61% (n=57), CMR = 84.7%
BCR-ABL/ABL>0.61% (n=222), CMR of 1.5%
p<0.0001
Individualized TKI selection - Efficacy
Inci
de
nce
of
CM
R
Marin D, et al. J Clin Oncol 2012;30(3):232-8.
Time from onset of imatinib therapy (years)
1%
Summary of pivotal phase III trials of approved TKI for
the frontline treatment of CML
Jabbour and Kantarjian. Am J Hematol 2018;93:442-59
High-dose imatinib and imatinib based
combinations : CML-study IV (10yr survival results)
Hehlmann et al. Leukemia 2017;31:2398-406
ASH 2017 # 897
Overall survival
Multivariate analysis for impact on survival (n= 1252)
Hehlmann et al. Leukemia 2017;31:2398-406
ASH 2017 # 897
Conclusions
- IM 400 mg monotherapy provides close to normal life expectancy
- Survival between IM400mg and any experimental arm was not different
DASISION 5 yr follow-up:
Cumulative MMR/ MR 4.5 rates over time
Cortes, et al. J Clin Oncol 2016;34:2333-40
ENESTnd 5 yr follow-up:
Cumulative MR 4.5 rates over time
A Hochhaus, et al. Leukemia 2016;30:1044-54
Takahashi, et al. Cancer 2016;122:3336-43
Propensity score matching analysis of dasatinib and
nilotinib as a frontline therapy with CML-CP
Cortes, et al. J Clin Oncol 2018;36:231-7
BEFORE 1 yr follow-up: Molecular response
RERISE 3 yr follow-up:
Cumulative MMR Rates over time
ASH 2017 # 317
Selecting a frontline treatment
• Efficacy of TKI in first-line clinical trials
• Patient’s age
• Patient’s comorbidities
• TKI toxicity profile
• Adherence
• Risk score
• BCR-ABL transcript type
• Additional chromosomal abnormalities (ACAs)
Bower et al. J Clin Oncol 2016;34:2851-7
Patient ≤ 50 yrs → Expected survival ≥ 30yrs
Durable CMR → Therapy discontinuation !!!
Elderly patients
Discontinuation → Less important
Swedish Cancer
Registry : 2662 CML pts
Published clinical studies of TKI discontinuation in patients with CP-CML
ASH 2017# Education
Selecting a frontline treatment
• Efficacy of TKI in first-line clinical trials
• Patient’s age
• Patient’s comorbidities
• TKI toxicity profile
• Adherence
• Risk score
• BCR-ABL transcript type
• Additional chromosomal abnormalities (ACAs)
Adverse effects of BCR-ABL1 inhibitors
Pleural/Lung problems
Dasatinib Dasatinib
Imatinib
Nilotinib
Cytopenias
Imatinib
Fluid retention
Nilotinib
Hyperglycemia Skin changes
Imatinib
Nilotinib
PAOD
Nilotinib
Steegmann JL et al., Leuk Lymphoma, 2012; 53:2351-61. Courtesy of Dr DK Kim
Unique profiles of clinically overt recurrent nonhematologic AEs in
patients with CML treated with BCR/ABL1-targeting TKIs
++, >20% of patients in at least 2 different studies
+, >5% of patients win at least 2 different studies
+/-, 1-5% in at least 1 study
-.<1%
Peter Valent et al. Blood 2015;125(6):901
Risk factors predisposing for the development of VAEs
Peter Valent et al. Blood 2015;125(6):901
Risk factors predisposing for the development of pleural effusion
Peter Valent et al. Blood 2015;125(6):901
Selecting a frontline treatment
• Efficacy of TKI in first-line clinical trials
• Patient’s age
• Patient’s comorbidities
• TKI toxicity profile
• Adherence
• Risk score
• BCR-ABL transcript type
• Additional chromosomal abnormalities (ACAs)
• adherence rates ↓ response rate ↓ survival rate ↓
Beaumont JL, et al. Blood. 2011;118(21):471 [abstract 1025].
Marin et al. J Clin Oncol. 2010;28(14):2381-2388.
Adherence is the critical factor for response
Administration of TKI
Imatinib Qd, with a meal
Dasatinib Qd, with no meal
Nilotinib Bid, fasting two hours before and one hour after each dose
Bosutinib Qd, with a meal
Radotinib Bid, fasting two hours before and after each dose
Ponatinib Qd, with or without a meal
Selecting a frontline treatment
• Efficacy of TKI in first-line clinical trials
• Patient’s age
• Patient’s comorbidities
• TKI toxicity profile
• Adherence
• Risk score
• BCR-ABL transcript type
• Additional chromosomal abnormalities (ACAs)
Calculation of relative risk
http://www.leukemia-net.org/content/leukemias/cml/cml_score/ http://www.leukemia-net.org/content/leukemias/cml/eutos_score/
SOKAL HASFORD EUTOS
Age 0.116 (age -43.4) 0.666 when age≥50 Non applicable
Spleen (cm below
costal margin, max
distance)
0.0345 (spleen-7.51) 0.042 x spleen 4 × spleen
Platelet (x 109/L) 0.188[(platelet count ÷ 700)2 -
0.563]
1.0956 when platelet
count >1,500
Non applicable
Blood myeloblasts (%) 0.0887 × (myeloblasts - 2.10) 0.0584 blast cells Non applicable
Blood basophils (%)
Non applicable 0.20399 when
basophils >3%
7 × basophils
Blood eosinophils (%) Non applicable 0.0413 × eosinophils Non applicable
Relative risk Exponential of the total Total x 1000 Total
LOW <0.8
≤780
≤87
INTERMEDIATE 0.8-1.2
781-1480 Non applicable
HIGH >1.2 >1480 >87 Sokal JE et al, Blood 1984; 63: 789-799
Hasford J et al, JNTL Cancer Inst 1998; 90: 850-858
Hasford J et al. Blood 2011;118:686-92
low Int High
16.9-25.6% ↑ 17.3-27.7% ↑ 19.2-21.8% ↑
2G TKI → more beneficial in patients with intermediate or high risk disease
Saglio and Jabbour. Leukemia & Lymphoma 2017
Response according to risk score assessment
Selecting a frontline treatment
• Efficacy of TKI in first-line clinical trials
• Patient’s age
• Patient’s comorbidities
• TKI toxicity profile
• Adherence
• Risk score
• BCR-ABL transcript type
• Additional chromosomal abnormalities (ACAs)
Impact of BCR-ABL transcript type on outcome in
patients with chronic-phase CML treated with tyrosine
kinase inhibitors
Jain et al. Blood 2016; 127:1269-75
** two most common transcripts: e13a2 (B2a2) and e14a2 (b3a2)
Jain et al. Blood 2016; 127:1269-75
b2a2 b3a2
Molecular responses (≤10% or ≤1%) for BCR-ABL at 3 and 6months
according to the type of BCR-ABL transcript (e13a2, e14a2, or both)
Jain et al. Blood 2016; 127:1269-75
Factors predictive of EFS including the type of BCR-ABL transcripts
Characteristics of CP-CML patients with major-route ACAs
Fabarius et al. Blood 2011; 118:6760-8
** Conclusion
Major route ACA at diagnosis are associated with a negative impact on survival
and signify progression to the AP/BP
Fabarius et al. Blood 2011; 118:6760-8
Cumulative incidences of MMR for patients with t(9;22), t(v;22), and
minor- and major-route ACAs
Conclusions
• A balance between the achievements of an early
response, long-term outcomes, potential AEs, and a
patient’s lifestyle are all key components for successful
therapy.
• Special considerations for patient-TKI pairing include
comorbidities, concomitant medications, age and sex,
risk factors, BCR-ABL1 transcript type and ACAs
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