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Upfront treatment of CML:How to select TKI?.pptx
1. Upfront treatment of CML:
How to select TKI?
Dr Pritish Chandra Patra
Associate Professor
Dept. of Clinical Hematology
IMS & SUM Hospital, Bhubaneswar
Which one to choose?
RED pill or BLUE pill
2. Epidemiology: SEER Database
1 to 2 new cases of CML are diagnosed per 100,000 people annually1
With the success of TKI therapy, the prevalence of CML is increasing annually2,3
1. Baccarani M, et al. Ann Oncol. 2009;20(suppl 4):iv105-iv107.
2. Rohrbacher M, Hasford J. Best Prac Res Clin Haematol. 2009;22(3):295-302.
3. Huang X, Cortes J, Kantarjian H. Cancer. 2012;118(12):3123-3127.
3. • ICON (Indian Cooperative Oncology Network) in 2010.
• 8115 patients data was presented and 18 centers.
• CML is one of the commonest adult leukemia in Indian population accounting for 30% to 60% of all adult
leukemias.
• Incidence of CML cases varied from 70% of all leukemia cases at IGIMS, RCC, Patna to 16.6% GCRI, Gujarat.
• This huge difference in incidence of CML cases:
• not population-based registries
• different cancer populations they cater to.
Indian data
Bansal S, Prabhash K, Parikh P. Chronic myeloid leukemia data from India. Indian J Med Paediatr Oncol. 2013 Jul;34(3):154-8.
4. • 2 decades back, managing CML was simple !
• Start Imatinib
• If it fails, Allogeneic Transplant !
• Now we have 6 TKI s, namely Imatinib, Nilotinib, Dasatinib, Bosutinib, Ponatinib and Asciminib
• Which one to choose as first Line ?
The journey so far
5. Overview
• Two decades of experience with imatinib and later-generation BCR::ABL1 TKIs in Ph+ve CML
• Important to discuss
• established guidelines on treatment options
• frontline CML therapy
• treatment aims
• response monitoring
• significance of the response milestones: ELN and NCCN
6. Targeted Therapy in the Post-Imatinib Era
Approved treatment
Imatinib
(Gleevec®/Glivec®)
FDA approval of imatinib
for all phases
of Ph+ CML1
2001
ENESTnd study meets its
primary endpoint; nilotinib
demonstrates superiority
over imatinib4,5
2009
1. Gleevec (imatinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
2. Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2012.
3. Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012.
4. Saglio G, et al. N Engl J Med. 2010;362(24):2251-2259.
5. Saglio G, et al. Blood. 2009;114(22) [abstract LBA-1].
6. Bosulif (bosutinib) [package insert]. New York, NY; Pfizer; 2012.
7. Iclusig (ponatinib) [package insert]. Cambridge, MA: Ariad Pharmaceuticals, Inc; 2012.
8. Synribo (omacetaxine mepesuccinate) [package insert]. North Wales, PA: Teva Pharmaceuticals, Inc; 2012.
9. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-scemblix-asciminib-patients-philadelphia-
chromosome-positive#:~:text=On%20October%2029%2C%202021%2C%20the,for%20adult%20patients%20with%20Philadelphia
Initial FDA
approval of
dasatinib2,a
2006
FDA approval of nilotinib for patients
resistant to or intolerant of prior therapy,
including imatinib3,a
2007
Dasatinib
(Sprycel®)
Nilotinib
(Tasigna®)
Nilotinib approved for first-
line use in patients with Ph+
CML-CP3,a
2010
Dasatinib approved for
first-line use in
patients with Ph+
CML-CP2,a
2010
2012
FDA approval of
bosutinib,6,a
ponatinib,7,a and
omacetaxine8,b for
patients resistant to
or intolerant of prior
therapy
Bosutinib
(Bosulif®)
Ponatinib
(Iclusig®)
2000 2010
Omacetaxine
(Synribo®)
2021
FDA approval of Asciminib for patients
with CML CP previously treated with >2
TKI and with T315I mutation9
2021
Asciminib
(Scemblix®)
Olverembatinib
7. Front line therapy
Primary aim
• To improve survival so that it matches that of a
normal population
Second aim
• Achievement of a durable deep molecular
response (DMR)
• Allow treatment discontinuation and potentially a
treatment-free remission (TFR) status
CCyR MMR DMR TFR
2 log reduction or
≤1 % on IS
MR3 or 3 log reduction or
≤0.1 % on IS
MR4 or 4 log reduction or ≤ 0.01% on IS
MR4.5 or < 0.0032% on IS
However, it is no indication that CML
has been eliminated !
8. Molecular response for CML
Vivian G. Oehler; First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?. Hematology Am Soc Hematol Educ
9. Available options
Imatinib Nilotinib
Dasatinib Bosutinib
Patients comply with the treatment
Monitored optimally
Minimal interruptions
Managed well at earliest signs of resistance
4 approved TKI for 1st line
All TKI near normal QoL and life expectancy
10. Established treatment goals and their significance
1. Hughes TP, et al. Blood 2014;123:1353-1360; 2. Jabbour E, et al. Blood 2014;123:494-500; 3. Hanfstein B, et al. Leukemia 2012;26:2096-2102; 4. Gambacorti-Passerini C, et al. Blood.
2017;130 [abstract 896]; 5. Baccarani M, et al. Blood. 2013;122:872-884; 6. Hochhaus A et al. Ann Oncol 2017;28:iv41-iv51; 7. Larson RA, et al. Blood. 2014;124 [abstract 4541]; 8. Hochhaus A,
et al. Leukemia. 2016;30:1044-1054; 9. Cortes JE, et al. J Clin Oncol. 2016;34:2333-2340; 10. Cortes JE, et al. J Clin Oncol. 2018;36:231-237.
• EMR is associated with higher rates of MR4.5 and improved OS and PFS1-3
• Rates of EMR (BCR-ABL1IS ≤ 10% at 3 months) are higher with 2G TKIs vs imatinib in 1L1,2,4
Early
Molecular
Response
• MMR at 12 months is considered to be an optimal response per treatment recommendations5,6
• Rates of MMR are higher with 2G TKIs vs imatinib in 1L4,7-10
MMR at
12 months
• Frequency of progression to AP/BC is lower with 1L nilotinib vs imatinib7; numerically fewer
patients have disease progression with 1L dasatinib vs imatinib9
Disease
Progression
• OS rates are high with all 1L TKIs4,8,9
• 2G TKIs are associated with fewer deaths due to disease progression than imatinib in 1L4,8,9
• Deaths due to CVEs are rare with imatinib and dasatinib8,9
• More deaths due to infections are seen with 1L dasatinib vs imatinib9
Overall
Survival
11. Overview of the 2020 ELN Recommendations
Key Updates Since the 2013 ELN Recommendations
CML, chronic myeloid leukemia; DMR, deep molecular response; ELN, European LeukemiaNet; TFR, treatment-free remission.
Hochhaus A, et al. Leukemia. 2020 Mar 3 [Epub ahead of print].
• Achievement of stable DMR and TFR to avoid life-long treatment is now considered
a treatment goal
CML Treatment Goals
• All target response milestones are now defined based on molecular response
levels
• Target response milestones are now the same for 1L and 2L therapy
• For patients aiming to achieve TFR, the optimal response at any time is now defined
as BCR-ABL1IS ≤ 0.01% (MR4)
Target Response Milestones
• The ELN has proposed contraindications for some TKIs
Recommendations Regarding Treatment Selection
• For the first time, the ELN has proposed criteria for attempting TFR outside of
clinical trials
TFR
12. Target Response Milestones for Frontline and Second-Line TKI Therapy
Optimal
BCR-ABL1IS Level
Warning
BCR-ABL1IS Level
Failure
BCR-ABL1IS Level
Baseline NA High-risk ACA, high-risk ELTS score NA
3 months ≤ 10% > 10%
> 10% if confirmed within 1 to 3
months
6 months ≤ 1% > 1-10% > 10%
12 months ≤ 0.1% (MMR) > 0.1-1% > 1%
Any time ≤ 0.1%a,b > 0.1-1%,
loss of MMRc
> 1%, resistance mutations, high-
risk ACA
ACA, additional chromosome abnormalities in Ph+ cells; BCR-ABL1IS, BCR-ABL1 transcript level on the International Scale; ELTS, European Treatment
Outcome Study Long Term Survival; MMR, major molecular response equivalent to BCR-ABL1IS ≤ 0.1%; NA, not applicable; Ph+, Philadelphia chromosome-
positive; TKI, tyrosine kinase inhibitor.
a For patients aiming to achieve TFR, the optimal response at any time is BCR-ABL1IS ≤ 0.01% (MR4).
b A change of treatment may be considered if MMR (BCR-ABL1IS ≤ 0.1%) is not achieved by 36-48 months.
c Loss of MMR indicates failure following TFR.
Hochhaus A, et al. Leukemia. 2020 Mar 3 [Epub ahead of print].
All target response milestones are now defined based on
molecular response levels
rather than cytogenetic or hematologic response
Key updates
since 2013
NCCN
Guidelines
2024
ELN
2020
13. Comparison of TKIs: which is the BEST?
Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring. Elias Jabbour, Hagop Kantarjian. Am J Hematol. 2022;97:1236–1256.
14. How to choose ?
Aim of therapy: survival or TFR
• Elderly: survival > TFR- Imatinib may be better
• Young: TFR > survival- 2G TKI
Cost of therapy & affordability
• Imatinib
• Generics
Co-morbidities
• Lung disease
• DM, HTN
• Hepatic or renal dysfunction
• Pancreatitis, enterocolitis, VOE
CML risk category
• Sokal or ELTS
• HR- 2G TKI > Imatinib
• LR- Imatinib > 2G TKI
• Advance disease
Management of chronic myeloid leukemia in 2023- common ground and common sense. J. Senapati et al. Blood Cancer Journal (2023) 13:58.
15. Scoring systems to guide!
Sokal Hasford
EUTOS ELTS
• Several risk scores help predict outcomes.
• Low- or intermediate-risk disease- expected to have optimal responses with
imatinib, dasatinib, nilotinib, or bosutinib.
• High risk disease- 2G TKI as frontline therapy may be more beneficial.
• Higher risk disease- a lower likelihood of achieving the early milestones of
CCyR and MMR and, particularly, higher risks of disease transformation to
AP-CML or BP-CML.
• Any of the TKIs currently approved for frontline CML therapy may be
selected.
• While 2G TKIs have demonstrated superiority over imatinib in relation to
early surrogate markers, imatinib is still highly effective in most patients with
CML.
Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring. Elias Jabbour, Hagop Kantarjian. Am J Hematol. 2022;97:1236–1256.
• Kinase domain mutation profile plays no role in selecting an initial TKI.
16. TKI resistance
• Incidence of primary resistance to frontline TKI therapy is 10%, and of secondary resistance 30%.
• German CML IV trial-
• 1551 pts, CML-CP, Imatinib, median follow up 10 yrs, 10yr OS 82%, relative survival rate 92%, , BP incidence 5.2%, 26.5% changed TKI:
10% due to, rest for toxicities
• MDACC-
• Dasatinib 50mg, median follow up 5yrs, 5yr OS 98%, AP/BP incidence 0%, primary or secondary resistance <5% (defined as BCR::ABL1
transcripts [IS] > 1% any time after 12 months of therapy)
• MDACC-
• Dasatinib 100 vs Imatinib trial in frontline-
• In our long-term frontline TKI therapy experience, the estimated 15-year OS rate (including any death,
regardless of cause) is about 75%. The CML-specific survival rate (considering only deaths from CML or
treatment complications) is >90% [33].
• Thus, frontline therapy with the existing TKIs achieves the primary endpoint of survival normalization for
most patients with CML.
Management of chronic myeloid leukemia in 2023- common ground and common sense. J. Senapati et al. Blood Cancer Journal (2023) 13:58.
17. Achievement of TFR
DMR: BCR::ABL1 transcripts- 0% or MR4 or MR4.5
Discontinuing the TKI after a sustained DMR of >2 years 3-year TFR rates- 40%–50%.
Discontinuation of TKI after a DMR of ≥5 years 5-year TFR rates- >80%.
Achievement of TFR has been estimated to be about 25–30%.
Management of chronic myeloid leukemia in 2023- common ground and common sense. J. Senapati et al. Blood Cancer Journal (2023) 13:58.
18. Special situation: Pregnancy
• Must be individualized.
• TKI should be discontinued in the first trimester, as soon as pregnancy is confirmed.
• Fetal ultrasonography should be performed immediately.
• Options of continuing or discontinuing treatment and continuation of pregnancy or not should
be exhaustively discussed.
• Teratogenicity of TKI is due to off-target- PDGFR inhibition during organogenesis.
• All TKIs are contraindicated throughout pregnancy.
• Although imatinib has been used safely in the second and third trimesters, insufficient
experience.
• More advance disease- termination of the pregnancy is considered.
• Low WBC count- CML treatment may not be required before delivery.
• Thrombocytosis- Aspirin and/or LMWH.
• Leucapheresis and/or IFNα are safe throughout gestation.
• Low-level secretion of TKI in breast milk contraindicates their use during breast-feeding.
19.
20. How to select TKI?
Vivian G. Oehler; First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?. Hematology Am Soc Hematol Educ Program 2020;
21. How to select TKI?
Vivian G. Oehler; First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?. Hematology Am Soc Hematol Educ Program 2020;