Chronic myeloid leukemia (CML) is a type of leukemia originating from abnormal bone marrow stem cells that are consistently associated with the BCR-ABL1 fusion gene. It accounts for 10-15% of myeloid leukemias and is more prevalent in males. CML progresses through three phases: chronic phase, accelerated phase, and blast crisis phase. Treatment involves tyrosine kinase inhibitors like imatinib, with the goal of controlling the disease long-term. Upfront hematopoietic stem cell transplantation may provide a cure but also carries risks of toxicity and mortality. Ongoing research is evaluating whether newer tyrosine kinase inhibitors or stopping imatinib after deep responses could improve outcomes while reducing costs and side

1. Chronic myeloid leukemia

2. Introduction
• Myeloproliferative neoplasm
• Originates in an abnormal pluripotent bone
marrow (8 M) stem cell
• Consistently associated with the BCR-ABL1
fusion gene located in the Philadelphia (Ph)
chromosome

3. Epidemiology
• Accounts for 10% to 15% of myeloid leukemia
• Constitutes 2–3% of leukaemias in children
• 0.7/million children/year 1 to 14 years of age
• 1.2/million children/year in adolescents
• Exceptionally rare in infancy
• Increased prevalence in males (1.2:1).
• The median age at presentation is 11 years.

4. 3 phases of the disease

5. Natural history of disease
• The median duration in CP in CHR is 4 yrs (Pre
imatinib era)
• AP to transformation to blast crisis (BC) is 6–18
months.
• Median survival in BC is 3– 9 months.
• The rate of transformation to BC has been
estimated
– 20–35% per year on hydroxycarbamide
– 10–20% per year for patients on IFN-α
– 1–1.5% per year for patients on imatinib
• On imatinib
– Incidence AP, BC and death of 5%

6. Differences between adult and childhood
CML
• Higher TLC ( 250 ×10 3 /µl vs 80- 150 ×10 3 /µl )
• Aggressive disease features
– Larger spleen
– Higher peripheral blast counts
– Lower hemoglobin levels
• 10% of cases present in advanced phase
• Goal of adult disease – control of disease
• Is control sufficient?

7. Is control sufficient?
• Longer life expectancy in child
• Long term toxicity in terms of fertility, growth
• 1–1.5% /yr transformation rate on imatinib
• Need of contraception
• No long term data on safety beyond 15 years
• Cost of lifelong imatinib treatment- 70000/yr
• Cost of MSD HSCT ~ 20 lakh- 40 lakh
• Cost over 40-50 yrs same- 20 % TRM

8. Questions in front
• Does upfront HSCT do any good?
• Does upfront 2G TKI are better than imatinib?
• Can we stop imatinib in CMR?

9. Upfront HSCT –evidence till date
85- 95 % CHR
60-65%CCR
30-35%MMR
Imatinib

10. Long term side effects
HSCT
• Myeloablative conditioning
• Loss of fertility
• Chronic GVHD
• Growth retardation
• Metabolic syndrome
• Second malignancies
• Now using RIC has
decreased this toxicity
• TRM – 20%
Imatinib
• Short term side effects-
• Lethargy and weight gain.
• Myalgias/cramps
• Bone pain
• Short stature
• Fertility and conception
issues
• No major life threatening
A/R

11. Bottom line
• No RCT in this
• Guidelines are still in imatinib as first line
• May come in future

12. 2G TKI vs Imatinib
• 2 G TKI only Dasatinib is approved for peds use
• 2GTKI have ↑ rate of achieving milestones
• ↑ molecular response
• Not translates into benefit in survival

13. Bottomline
• 2G TKI result in better rate to achieve milestones
• But no survival advantage
• More costly
• No upfront role
Imatinib is the first line drug at this moment

14. Can we stop Imatinib
• Only ↓trials this should be done
• 2 yrs of CMR (<0.01) can be given trial of
discontinuation
Monitor MRD every month for 12 month after stopping TKI, then 2- 3 monthly

15. Can we stop Imatinib- indications to
restart
• Recommend- re-starting TKI -short doubling
time(< 10 days)
• Molecular recurrence
• Majority of patients regain UMRD in 6 months
• Stopped -second time after UMRD for at least 12
months
• 25% remained off treatment without loss of
MMR.

16. Diagnosis
Diagnosis of CML – from
bone marrow
To r/o AP or BC phase
(Blast + promyelocytes <
20 %)

17. Cytogenetics
• Conventional karyotyping- sensitivity 5%
• Not detects cryptic translocation
• Useful to assess assc sec chromosomal
changes, clonal evolution preceding AP
• Interphase FISH
• Not needs metaphase extraction, rapid
• Picks up cryptic translocation
• Sensitivity- 0.5%

18. RQ PCR for BCR- ABL
• At diagnosis and 3 months- rate of fall in
transcript
• 1 log reduction at 3 months predicts 70% vs
13% chance of achieving MMR

19. Indications for KD mutation analysis
• CHR not achieved by 3 months
• Major CyR not achieved by 6 months
• CCyR not reached by 12 months
• Lose of CHR or CCyR at any point
• ≥ 10-fold rise in BCR-ABL1 transcript levels
• Presenting with accelerated or blast phase.

20. Monitoring during treatment

21. Monitoring during treatment

22. Definitions of response

23. Timeline to response

24. Treatment of chronic phase

25. Treatment of accelerated phase

26. Treatment of blast crisis phase

27. Imatinib dose and administration
• 260 – 340mg/m 2
• Take it in the morning with breakfast.
• To be taken in a sitting position
• Tablets may be dispersed in water or apple
juice using 50 ml for 100 mg tablet, 200 ml for
400 mg tablet.

28. Rate of normalization of counts post
imatinib
• WBC count usually starts to fall in 1–2 weeks
• WBC -normalizes in 6 weeks
• Platelet counts usually normalize after 1–3
weeks
• 3–6 weeks if the platelet count is >700× 10 9/l.

29. Toxicity of imatinib

30. Management of hematological toxicity
• Anaemia: transfusion or erythropoietin rather
than dose reduction.
• Neutrophils (ANC)<1000: stop for up to 2
weeks
– Restart when ANC> 1000.
– Consider G-CSF if persistent neutropenia
– Reduce dose by 20% for persistent neutropenia.
• Platelet counts <50000-stop
– Restart when platelets >100000
– Reduce dose by 20% if recurrent.

31. Management of other toxicity