- Before imatinib therapy, the median survival time for CML was 3-7 years and mortality rates were 10-20%. With imatinib and newer TKIs like nilotinib and dasatinib, mortality has decreased to 2% and 8-10 year survival rates are now 85-93%. - Achieving a complete cytogenetic response or major molecular response on TKI therapy is associated with lower risk of disease progression. Allogeneic stem cell transplant remains curative but is now typically reserved for cases where two or more TKIs have failed or the disease progresses to accelerated or blast phase. - TKIs have significantly improved survival but can cause side effects affecting quality

1. MANAGEMENT OF CML
Dr Suman Roy
PGT - Medicine

2. PROGNOSIS AND CML COURSE
Before imatinib era
• First 2 yrs - mortality 10%
• Thereafter - 15–20%.
• MST was 3–7 years (with HU-bslfn IF-α)
Without allogeneic SCT
• Transformation - Death from accelerated or blastic phases.
• The disease stability – unpredictable
• sudden transformation to a blastic phase
• DEATH

3. With imatinib therapy
• Mortality -decreased to 2%
• 8 to 10-year SR is now - 85% or 93%
• Disease course -quite predictable
• First 2yrs of TKI therapy
- rarely sudden transformations
-noted (1–2%)
• usually lymphoid blastic transformations
respond to combinations of chemotherapy and
TKIs followed by allogeneic SCT

4. • Second-generation TKIs (nilotinib, dasatinib) -frontline
therapy have reduced -the incidence of transformation
• first 2–3 years from 6–8% with imatinib to
• 2–4% with nilotinib or dasatinib.
• Disease transformation to accelerated or blastic phase
is rare on continued TKI therapy,
• estimated at <1% annually in years 4–8 of follow-up on
the original imatinib trials.

5. Develop resistance
• in the form of cytogenetic relapse
• hematologic relapse
• subsequent transformation
Rather than
• previously feared sudden transformations without the
warning signals of cytogenetic-hematologic relapse.

6. Pretreatment prognostic factors
These have included
• Older age
• Significant splenomegaly
• Anemia
• Thrombocytopenia or thrombocytosis,
• High percentages of blasts and basophils (and/or
eosinophils)
• Marrow Fibrosis
• Deletions in the long arm of chromosome 9
• clonal evolution and others.

7. in the era of imatinib
(Treatment-related prognostic factors most important)
• Achievement of complete cytogenetic response
is major therapeutic endpoint (only endpoint)
• Achievement of a major molecular response is associated
with decreased risk of events (relapse) and CML
progression
• may predict event-free survival
• but has not been associated with survival prolongation.

8. • Among patients in CCR survival is similar
(Independent of major molecular response or not)
• Due to the efficacy of salvage TKI therapies,
which are and should be implemented at the
first evidence of cytogenetic relapse.

9. • Achievement of complete molecular response
(undetectable BCR-ABL1 transcripts)
• particularly when durable (>2 years), may offer the
possibility of durable molecular response
(molecular cure rather than functional cure) in the
context of investigational trials
• and may allow temporary therapy interruption in
women eager to have babies.

10. Treatment Failure ???
• The lack of achievement of major or complete
molecular responses should not be considered
as “failure” of a particular TKI therapy
• and/or Not an indication to change the TKI or
to consider allogeneic SCT.

13. Treatment
• Hydroxyurea-busulfan-- 3–4 years
• IF-α therapy (1986)------ 6–7 years
• TKI (Since 2001) ---- 10-year survival 85%.

14. TKIs
• First Generation
Imatinib (Gleevec)
• Second Generation
Nilotinib(Tasigna)
Dasatinib (Sprycel)
Bosutinib (Bosulif)
• Third Generation
Ponatinib (Iclusig)

15. • 6 agents approved by the U.S. FDA
Five oral BCR-ABL1-selective TKIs:
1. Imatinib (Gleevec) -- 400 mg OD
2. Nilotinib(Tasigna) -- 300mg BD empty stomach
3. Dasatinib (Sprycel) – 100 mg OD
4. Bosutinib (Bosulif)-- 500 mg daily and ponatinib
5. Ponatinib (Iclusig). -- (45 mg daily).

16. Nilotinib
• 30 times more potent
Dasatinib and bosutinib
• They are Dual SRC-ABL1 TKIs
• Dasatinib is reported to be 300 times more potent
• Bosutinib 30–50 times more potent than imatinib).
Ponatinib
• is effective against wild-type and mutant BCRABL1 clones.
• It is unique in being the only currently available BCRABL1
TKI that is active against T315I, a gatekeeper mutant
resistant to the other four TKI

17. • Accelerated and Blastic phase
Imatinib
Dasatinib
Bosutinib
Ponatinib
• Chronic and Accelerated phase.
Only Nilotinib

18. OMACETAXINE (SYNRIBO)
• The 6th approved agent
• a protein synthesis inhibitor
• more selective inhibition
of the synthesis of the BCR-ABL1 oncoprotein.
• Approved for chronic- and accelerated-phase
• after failure of two or more TKIs,
• 1.25 mg/m2 s.c BD for 14 days induction and for 7 days
for consolidation-maintenance.

19. Side effects
• mild to moderate with long-term TKI therapy
• affect the patient’s quality of life.
• Serious side effects < 5–10%
Renal dysfunction and renal failure
Pulmonary hypertension - with dasatinib
Systemic hypertension
Hyperglycemia and diabetes
mid- and small-vessel vasoocclusive and vasospastic
events (nilotinib and ponatinib)

20. Imatinib
• fluid retention,
• weight gain,
• nausea,
• diarrhea,
• skin rashes,
• periorbital
• edema,
• bone or muscle aches, fatigue, and others (rates
of 10–20%).

21. Dasatinib
• Myelosuppression (20–30%),
particularly thrombocytopenia
• Pleural (10–25%) or pericardial effusions (≤5%)
• Prolongation of the QTc interval
Nilotinib
• Hyperglycemia(10–20%)
• Pruritus and skin rashes
• Headachesrare events of pancreatitis (<5%).
• Prolongation of the QTc interval

22. Bosutinib
• early and self-limited gastrointestinal
complications like diarrhea (50–70%).
Ponatinib
• skin rashes (10–15%), pancreatitis (5%),
elevations of amylase/ lipase (10%), and
vasospastic/vasoocclusive events (10–20%).

23. Side effects
• These side effects can often be dose-
dependent and are generally reversible with
treatment interruptions and dose reductions.

24. ALLOGENEIC STEM CELL TRANSPLANT
• Allogeneic SCT, a curative modality in CML
• is associated with longterm survival rates of 40–60% when
implemented in the chronic phase.
• early (1-year) mortality rates - 5–30%.
• 5- to 10-year survival rates - 50–60%
• 10–15% of patients die in the subsequent 1–2 decades -
subtle long-term complications of the transplant

25. Choice and Timing of Allogeneic SCT
• SCT was considered first-line CML therapy before 2000.
• Now, after first-line TKI failures
THE OPTIMAL TIMING
• Among patients with or evolve to blastic phase
• combinations of chemotherapy and TKIs should be used
to induce remission
• followed by allogeneic SCT as soon as possible.

26. Patients relapse in chronic phase
The treatment sequence depends on several factors
• Patient age and availability of appropriate donors
• Risk of allogeneic SCT
• Presence or absence of clonal evolution and mutations
• Patient’s prior history and comorbidities
• Patient and physician preferences
Patients with T315I mutations at relapse
Should be offered ponatinib and considered for
allogeneic SCT

27. Allogeneic SCT: when can be delayed?
• Patients without clonal evolution or mutations at relapse
• Who achieve a complete cytogenetic response with TKI
salvage
• Have long-lasting complete remissions
May delay the option of allogeneic SCT to third-line therapy.

28. MONITORING THERAPY IN CML
• Achievement of CCR by 12 m of imatinib therapy and
its persistence later- consistent PF associated with
survival, main therapeutic endpoint in CML.
• Failure to achieve by 12 m or occurrence of later
cytogenetic or hematologic relapse considered as
treatment failure and an indication to change therapy
• Because salvage therapy with other TKIs
reestablishes good outcome, it is important to ensure
patient compliance to continued TKI therapy and
change therapy at the first sign of cytogenetic
relapse.

29. TREATMENT OF ACCELERATED AND BLASTIC PHASES
• Patients in accelerated or blastic phase may receive
therapy with TKIs
• Preferably second- or third-generation TKIs
(dasatinib, nilotinib, bosutinib, ponatinib)
alone or in combination with chemotherapy
• To reduce the CML burden, before undergoing
allogeneic SCT.

30. OTHER TREATMENTS AND SPECIAL THERAPEUTIC CONSIDERATIONS
Interferon α
• Interferon α was a standard of care before 2000.
• Today, it is considered in combination with TKIs
Chemotherapeutic Agents
Hydroxyurea and busulfan were commonly
used chemotherapeutic agents in the past.

31. Others
• Splenectomy is occasionally considered to alleviate
symptoms of massive splenomegaly and/or
hypersplenism
• Leukapheresis is rarely used in patients presenting
with extreme leukocytosis and leukostatic
complications
• high-dose cytarabine or high doses of hydroxyurea
in Tumor lysis management

32. In Pregnency
• should discontinue TKI therapy immediately.
teratogenicity of imatinib.
Among 125 babies 3 babies were born with
ocular, skeletal, and renal malformations
• There are no or little data with other TKIs.
Control of CML during pregnancy
1st Trimester leukapheresis for severe symptomatic
leukocytosis
After 1st Trimester with hydroxyurea

33. THANK YOU