CML

1. ELN GUIDELINES FOR CML
2020
Dr. Chinmayee Agrawal
Moderator: Dr. Nalini Kilara
15.03.2021

2. OVERVIEW
 Introduction
 Methods
 Diagnostic work up
 Epidemiology
 Prognostic factors
 Molecular response definitions
 Monitoring response
 First and Second Line Treatment
 Allo SCT
 Treatment free Remission
 Pregnancy and Parenting

3. INTRODUCTION
 Newly diagnosed Ph+ CML in CP phase very close life
expectancy to age matched individuals.
 Several TKIs approved for treatment of CML
 Concept of Treatment free remission
 Methods:
 34 experts from Europe and Asian Pacific areas
 International meetings
 Goal of treatment: Normal survival
Good quality of life
Without life long treatment

4. DIAGNOSIS:

6. EPIDEMIOLOGY
 Median age: 57years (Western)
<50years (Asia and Africa)
 Bimodal distribution:
 >70yrs: 20%
 Children and adolescents: <5%
 Age is an important variable

7. PROGNOSTIC SCORING
1. SOKAL Score
2. EURO Score
3. EUTOS score

8. NEW EUTOS LONG TERM SURVIVAL SCORE

9. MOLECULAR RESPONSE DEFINITIONS:
 International Scale: Ratio of BCR-ABL1 transcripts
to ABL1 transcipts
 Reported as BCR-ABL1 % on Log scale
 1%: Decrease of 2 Logs
 0.1%: Decrease of 3 Logs
 0.01%: Decrease of 4 Logs
 0.0032%: Decrease of 4.5 Logs
 0.001%: Decrease of 5 Logs

11. NCCN 2021

12.  CCyR: BCR-ABL1 ≤1%
 MMR or MR3: ≤0.1%
 MR4: ≤0.01%
 MR4.5: ≤0.0032%
 Complete molecular response term should be avoided
 Substituted by Molecularly undetectable leukemia

13. RESPONSE MONITORING
 CBC and Differential cell count: Every 2 weeks
 QPCR on blood cells; BCR-ABL1: 3 monthly
 Cytogenetics by CBA: Atypical translocations
 FISH monitoring: Atypical transcripts

14. FIRST LINE TREATMENT
 Short course of hydroxyurea
 Tyrosine kinase inhibitors
 4 TKIs as first line: Imatinib, Nilotinib, Dasatinib,
Bosutinib
 Radotinib: South Korea

15. IMATINIB
 1st generation TKI
 IRIS Study:
 Higher rates of Cytogenetic and Molecular response
 Better PFS and OS
 Standard dose: 400mg OD

16.  CP: 300mg can be used if 400mg not well tolerated
 AP: 400mg twice a day
 Progression of disease: Change to second
generation TKI

17.  Early molecular response 3 and 6 months : 60-80%
 1 and 5 years, MMR : 20-59% and 60-80%
 5 year probability of achieving DMR: 35-68%
 Change of Imatinib: 26.5% at 10 years to 37-50% at
5 years
 5 year PFS and OS : 80-90% & 90-95%

18.  10 year OS: 82 and 85%
 Leukemia related death rate: 6%
 Cause for Poor tolerance: Early fluid retention
GI symptoms
Muscle cramp
Joint pain
Skin rash
Fatigue

19. DASATINIB
 2nd generation TKI
 More potent than Imatinib
 Active against several Imatinib resistant BCR-ABL
mutants.

20. DASISION TRIAL
 Dasatinib 100mg vs Imatinib 400mg
 Early molecular response rate: 84%
 MMR rate by 1 year: 46%
 5 year cumulative probabilities MMR 76%
MR4.5 : 42%
 PFS, OS and rate of changing similar

21.  Dose:
 CP- 100mg once daily
 Advanced phase- 70mg twice daily
 Toxicity: Recurrent pleural effusions
Pulmonary arterial hypertension

22. NILOTINIB
 2nd generation TKI
 More potent than Imatinib
 Inhibits several Imatinib resistant BCR-ABL1
mutants

23. ENESTND TRIAL:
 Nilotinib 300mg BD vs Imatinib 400mg OD
 5 and 10 year cumulative probabilities
MMR: 77% and 82.6%
MR4: 66% and 73%
MR4.5: 54% and 64%
 5 and 10 year OS: similar
 Change of primary treatment : 40% vs 50%
 ENESTchina similar response data by 1 year

24.  Dose:
 1st line treatment: 300mg twice daily
 2nd Line: 400mg twice daily
 GIVEN BEFORE FOOD
 Contraindications:
 Coronary hear disease
 Cerebrovascular accidents
 Peripheral arterio-occlusive disease

25. BOSUTINIB
 3rd generation TKI
 More potent than Imatinib
 Inhibits several BCR-ABL1 mutants

26. BFORE TRIAL
 Bosutinib 400mg OD vs Imatinib 400mg OD
 Follow up <2yrs
 Early molecular response: 75%
 1 year MMR: 47%
 Dose:
 1st line: 400mg once
 2nd line: 500mg once daily
 Side effects: Diarrhoea
Transient elevation of transaminases

27. RADOTINIB
 2nd generation TKI
 Approved in South Korea structurally similar to
Nilotinib
 Rerise Trial: Radotinib vs Imatinib
 Significantly higher molecular response rates
 Dose: 300mg twice daily
 Complications: Increase in transaminases levels

28. INTERFERON ALPHA
 Pre TKI era: Treatment of choice
 Re-emerge as a therapeutic option CP-CML
 Combination of Imatinib with Peg IFN alpha
Deeper and faster responses
 Ongoing trials: Peg IFN alpha with Nilotinib

30. GENERICS AND COST EFFECTIVENESS
 Imatinib widely available
 Dasatinib in Line
 Enhanced vigilance for 1st six months
 Life long cost: Deciding 1st Line treatment

31. SECOND LINE TREATMENT
 Failure or Resistance
 Accompanied by BCR-ABL1 KD mutations
 Intolerance or treatment related complications
 Criteria: Age
Comorbidity
Toxicity of first TKI
 Absence of alternatives: TKI should be continued
 All 1st line TKIs can be used
 Definition of response remains the same

32. PONATINIB
 3rd generation TKI
 More potent than all other TKIs
 Approved: BCR-ABL1 mutation with CML Resistant
to 2or more TKIs
 T315I: Only approved Ponatinib

33.  Dose:
 FDA approved: 45mg OD
 Lesser degree of Resistance: 30mg or 15mg
 Side effects: Cardio vascular toxicity
 Control of hypertension
 Hyperlipidemia
 Diabetes
 Smoking cessation

34. ADVANCED PHASE CML
 End phase CML:
 Early progression
 High risk additional chromosomal aberrations
 Late progression with failing hemotopoiesis
 Blast cell proliferation
 Diagnosis:
 Percentage of blasts: 20% or 30%

36. ALLOGENIC STEM CELL TRANSPLANTATION
 First CP:
 Disease resistant or intolerant to multiple TKIs
 Inadequate recovery of normal hematopoesis
 Resource poor Countries: Allo-SCT priority
 Resistant to 2GTKI
 Failure to Ponatinib at 3months
 CP2: Allo-SCT

37. TREATMENT FREE REMISION
 DMR defined as BCR-ABL1 levels of MR4 and
MR4.5
 Attempt at treatment discontinuation may be
considered
 STIM 1 trial:
 38% maintained molecular remission at 77 months
 Eligibility criteria: Stopping treatment MR4.5
sustained for 2 years

39. PREGNANCY AND PARENTING
 Men taking Imatinib, Bosutinib, Dasatinib or
Nilotinib: No risk of congenital abnormalities
 Women: TKI treatment 1st trimester is discontinued
 Teratogenicity: PDGFR inhibition during
organogenesis
 Dasatinib: Hydrops fetalis

40.  Advanced Stage: Termination of Pregnancy
 Low TLC count: Treatment may not be required
 Thrombocytosis: Acetyl salicylic acid and/or LMWH
 Leucapheresis & IFN alpha: Gestational safe
 TKIs are contraindicated during Breast Feeding

41.  Trial of TFR: safely discontinue TKIs
 MMR Lost: Likely to reach term without restarting
treatment
 Women without DMR desiring pregnancy:
Substitute with INF alpha

42. DISCUSSION

43.  4th version of ELN management recommendations
 Imatinib vs 2GTKI/Increase dose/INF alpha/ Low
dose cytarabine failed to improve OS
 Deeper molecular responses occurred more rapidly
 Patients die of CML unrelated causes than from
CML itself

44.  Chronic low grade fatigue and muscle cramp main
concern to those on treatment
 No final consensus, advisability of changing therapy
with stable CCyR or MMR.
 But in whom the level of DMR(<MR4) insufficient to
warrant consideration of discontinuation

45.  ENESTcmr Trial:
 Persistent molecular disease: achieved CCyR to
continue Imatinib vs Nilotinib
 Rate of achieving MR4.5 higher
 No information on TFR subsequently
 Ongoing Trial: SUSTRENIM
 Info on TFR rates after 4 years of Nilotinib or Imatinib
 Treatment cessation will be offered fter atleast 1 year in
MR4

46.  New ELTS risk score predicting the rate of death
from CML in TKI treated patients
 Good quality molecular testing has replaced
cytogenetic monitoring
 Disease progression:
 BM aspirate for cytogenetic clonal evolution
 BCR-ABL1 KD mutation

47.  Generic Imatinib available worldwide
 T315I Mutations: Ponatinb
 Resistant or Intolerant to 2or more TKI: AlloSCT
 All TKI teratogenic and C/I during pregnancy
 Ongoing studies: PEG-IFN alpha with TKI