This document provides an overview of the treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). For AML, it discusses pre-treatment evaluation, induction therapy including various chemotherapy regimens, post-remission consolidation therapy stratified by risk factors, and management of relapsed or refractory disease. It also covers special situations in AML including differentiation syndrome, tumor lysis syndrome, and hyperleucocytosis. For CML, it outlines prognostic scoring, treatment goals, available tyrosine kinase inhibitors and their dosing and side effects, monitoring response levels, and options for treatment discontinuation or allogeneic stem cell transplant.

1. TREATMENT OF
ACUTE &CHRONIC
MYELOID LEUKEMIA
-S.PAVAN SAGAR
Under the guidance of
Dr.Srikanth Sir Professor and chief Unit 6
Dr.Jeevitha madam Asst Professor

2. ACUTE MYELOID LEUKEMIA

3. PRE-TREATMENT EVALUATION
• Thorough History and physical examination
• Identify comorbid conditions
• Physical functioning and performance status
• Laboratory studies and Bone marrow studies
• HLA typing
• Proper counselling of patients and family

6. Broadly treatment divided into
INDUCTION PHASE
POSTREMISSION CONSOLIDATION
PHASE
Achieve remission
Patients should be categorised according to
• Age
• Physical fitness
• Cytogenetics
• Molecular risk

7. Induction Therapy in medically fit adults
With mutated FLT3 Without mutated FLT3
Cytarabine 100-200mg/m2/d
IV 7days +
Daunorubicin 60-
90mg/m2/d IV 3 days
Cytarabine 100-
200mg/m2/d IV 7days +
Daunorubicin 60-
90mg/m2/d IV 3 days +
MIDOSTAURIN orally
50mg D8 -D21 or
Quizartinib

8. GEMTUZUMAB OZOGAMICIN:
• Anti cd 33 MAB
• For CD 33 + AML as add on drug
• Hepatotoxic
IDH inhibitors
• Ivosidenib and
Enasidenib

9. INDUCTION REGIMENS

10. Nadir Bone marrow assesment
• Done at Day14 –Day22 following primary induction therapy
Hypoplastic
marrow
Persistent
blasts
Adjunctive care Reinduction with
Cytarabine+/-Anthracyclines

11. Response evaluation
• After ANC >1000;usually 4 weeks after induction therapy

12. Management of MEDICALLY UNFIT /OLDER PATIENTS

13. POSTREMISSION THERAPY
FAVOURABLE
RISK
INTERMEDIATE RISK ADVERSE RISK
Chemotherapy
3 cycles of
Intermediate
dose/standard
dose cytarabine
Allogenic HCT or
Chemotherapy
Allogenic HCT
Patients intially treated with venetoclax or lower intensity chemo:
Continue the same in post remission phase

16. GRAFT VERSUS
LEUKEMIA

17. ACUTE PROMYELOCYTIC LEUKEMIA

18. INDUCTION THERAPY
LOW RISK
WBC <=10000
HIGH RISK
WBC>10000
ATRA
45mg/m2/d +
ATO 0.15mg/kg/d
ATRA +
ANTHRACYCLINE
Post remission with ATO 2
cycles followed by
ATRA +Daunorubicin
Post remission
with ATO

19. Treatment options post transplant AML RELAPSE

20. Tumor lysis syndrome

21. •Oncologic emergency due to tumor
lysis with release of
intracellular potassium, phosphate,
and nucleic acids (source of uric acid)
into the bloodstream
• Generally occurs with a high tumor
burden and with initiation of
cytotoxic therapy (i.e. induction
chemotherapy

22. Hyperleucocytosis/Leucostasis
• WBC count greater than 1lakh/mm3
• Seen in 10-20percent patients of AML(M4 &M5)
• Due to increased blood viscosity And blast cell plugs in
micro circulation with coexistent inflammation
• Pulmonary and neurologic manifestations
• Cytoreduction with Chemotherapy with adequate
hydration
• Other options Hydroxyurea and Leukapheresis

24. Differentiation syndrome

25. CHRONIC MYELOID LEUKEMIA

26. • Chronic myeloid leukemia is a myeloproliferative neoplasm , in which cells of
the granulocytic lineage are the predominant proliferative component.
• CML is associated with the Philadelphia chromosome, t(9;22)(q34;q11),
which creates a BCR::ABL1 fusion gene.
• This genetic abnormality encodes the constitutively active tyrosine kinase
BCR::ABL1, which is essential to the development of CML and is the primary
target for treatment of CML.

28. Prognostic score
• CML prognosis is estimated using one of the validated CML
clinical scoring systems.
• Validated CML clinical scoring systems are:
• ELTS (EUTOS Long Term Survival) score
• Sokal
• Euro (Hasford)
• EUTOS

29. Goals of care
• The goals of care for patients with CML are
• to achieve clinical, cytogenetic, & molecular remission;
• maintain long-term disease control;
• avoid progression to advanced disease ie, accelerated phase [AP] or
blast phase [BP],
• optimizing quality of life by limiting treatment-related toxicity.
• Many patients and clinicians also consider achieving a treatment-free
remission (TFR) as an important goal.
• Palliation of symptoms may be the goal for severely debilitated or frail
patients.

30. Treatment options
• Tyrosine kinase inhibitors
• Other agents
• Allogeneic hematopoietic cell transplantation (HCT)

32. GENERATION DRUG POTENCY UNIQUE FEATURES
FIRST IMATINIB
SECOND DASTINIB 300x Inhibits SRC kinase too
NILOTINIB 30x Only TKI not approved for CML-BC
Only TKI to be taken on empty
stomach
BOSUTINIB 30-50x Inhibits SRC kinase too
No activity against c-kit or PDGFR
THIRD PONATINIB Only available BCR-ABL1 TKI active
against T315I.
PROTEIN SYNTHESIS
INHIBITOR
OMACETAXINE
MEPESUCCINATE
Approved for failure of >=2 TKIs

33. Doses & Toxicities
1st line indications Adverse effects
Imatinib 400 OD All phases Fluid retention, git, muscle
aches, pigmentation
Dasatinib First-line: 100 mgOD
Salvage :
• 100 mg daily in
chronic phase
• 140 mg in
transformation
All phase Myelosuppression,
pleural&pericardial effusion,
pulmonary htn
Nilotinib First-line: 300 mgBD
(ON EMPTY STOMACH)
Salvage :400 mg BD
All phases except blastic
phase
Bosutinib First-line: 400 mg OD
Salvage :500 mg OD
All phases
Ponatinib 45 OD -15 OD ( if
cytogenetic response is
achieved)
Omacetaxine

34. TKI
• IMATINIB (1ST GEN)
• Less potent than other TKI, but overall survival is no different
• Off patent since Nov 2016 – 10x cheaper!
• 5-year Deep Molecular Response rate 35-70%
• TIDAL2 Study – switch to 2nd gen TKI if not <10% at three months
• C/I: No absolute contraindications. Observe pts with renal or cardiac
impairment closely
• SE: Rash, oedema, diarrhoea, cramps, joint pain, fatigue. Probably safer than
the others
•

35. • DASATINIB (2ND GEN)
• More potent than imatinib, 4-year MMR-rate approx. 75% compared to 60% imatinib
• C/I: Respiratory failure, Pleuro/pulmonary/pericardial disease
• SE: 3-5% cardiac, 5% Pleural effusion per year, Pul HTN, opportunistic infections
(neutrophil dysfunction), platelet function defect
• NILOTINIB (2ND GEN)
• More potent than imatinib, 4-year MMR-rate approx. 75% compared to 60% imatinib
• C/I: History of coronary artery disease, stroke, periph vascular disease or pancreatitis
• SE: 20% cardiac (dose-related), 5% pancreatitis, hyperglycaemia

36. • BOSUTINIB (2ND GEN)
• More potent than imatinib
• C/I: Nil specific
• SE: 30% diarrhoea, transient transaminitis, pancreatitis, liver &renal dysfunction.
• PONATINIB (3RD GEN)
• More potent that 2nd generation TKI’s
• Indicated in T315I mutation, which is resistant to most other TKI
• Dose 15-45mg daily
• Option to reduce to 15mg once BCR-ABL/ABL <1%, majority will continue to respond
• SE: 30% cardiac (likely dose-related risk), skin rash, more incidence of arterio-
occlusive events.

37. When to change TKI
• Response : atleast CCyR should be there.
Do not change for absence of MMR or DMR.
• Tolerance : well tolerated without grade 3 or 4 side effects or with
bothersome chronic effects.
• Hence , do not change TKI or consider allo-HCT unless cytogenetic
relapse or intolerable side effects.

38. Terminologies
• Complete CyR (CCyR), defined as <1% BCR-ABL1 positive
nuclei of at least 200 cells.
• Major Molecular Response (MMR, MR3.0)
• <0.1% BCR-ABL1 transcripts

39. • Deep Molecular Response (DMR)
• MR4.0 defined as:
• either i) detectable disease with <0.01% BCR-ABL1 IS
• or ii) undetectable disease in cDNA with >10,000 transcripts.
• MR4.5 defined as:
• either i) detectable disease with <0.0032% BCR-ABL1 IS
• or ii) undetectable disease in cDNA with >32,000 transcripts.
• MR5 defined as:
• either i) detectable disease with <0.001% BCR-ABL1 IS
• or ii) undetectable disease in cDNA with >100,000 transcripts.

40. Response in CML
• HAEMATOLOGICAL :
• Complete haematological
response:
• Leucocyte count < 10000/l
• Basophils <5%
• No myelocytes, promyelocytes or
blasts
• Platelet count <4.5lakh/L
• Spleen not palpable
• CYTOGENETIC:
• Complete cytogenetic response:
no Philadelphia chromosome on
FISH
• Partial cytogenetic response: Ph
chr in 1-35% metaphases.
• Minor cytogenetic response: Ph
chr in 36-65% metaphases.
• Minimal cytogenetic response:
Ph chr in 66-95% of metaphases.

41. Molecular response in CML
measured by quantitative reverse transcriptase PCR
Log reduction BCR-ABL % on IS Molecular response grading
0 (base line) 100%
1 10% MR1
2 1% MR2
3 0.1% MR3 (MMR)
4 0.01% MR4
4.5 0.0032% MR4.5
5 0.001% MR5
MMR-MAJOR MOLECULAR RESPONSE
DMR-DEEP MOLECULAR RESPONSE

42. Correlation of Cytogentic response with
molecular response
Cytogenetics Response name PCR (BCR-ABL% IS)
< 35% metaphases PCyR (MR1) <=10%
0% metaphases CCyR (MR2) <=1%
MMR (MR3) <=0.1%
MR4 <=0.01%
MR4.5 <=0.0032%
MR5 <=0.001%

43. Response to treatment
• Optimal response associated with best long-term outcome —
achieving MMR (<0.1%) predicts a CML-specific life expectancy
the same as that of the general population.
• Treatment failure can be:
• Primary – failure to meet expected response at a given time (see table)
• Secondary – loss of response (at any time: Loss of CHR / CCyR / MMR
or CCA/Ph+)
• Initial Monitoring
• Fortnightly FBC until complete haematologic response (normal WBC),
and to assess for haematological toxicity.

44. TIME POINTS OF RESPONSE IN CML
Optimal Warning Failure
Baseline - High-risk ACA
High-risk ELTS
-
3 months <10% >10% >10%
6 months <1% >1-10% >10%
12 months <0.1% >0.1-1% >1%
Anytime <0.1% loss of<0.1% >1% resistant mutations
/ high risk ACA

45. Discontinuation of TKI &
Treatment free remission

46. Other drugs
• Hydroxyurea –
A short course of hydroxyurea ( 20 - 40 mg/kg/day) in patients with
significant leukocytosis (eg, >100,000/microL), systemic symptoms, or symptomatic
splenomegaly
while awaiting results from cytogenetic or molecular confirmation of the diagnosis of
CML or for management of advanced phase CML while awaiting BCR::ABL1 mutation
analysis.
• Interferon –
Interferon (IFN) alfa can be given to patients who are diagnosed with CML during
pregnancy.
• TKIs are contraindicated in women who seek to become pregnant and in the first trimester of
pregnancy because of increased rates of miscarriage and fetal abnormalities.
• IFN alfa is considered safe during pregnancy.
• Omacetaxine mepesuccinate – This agent, previously known as homoharringtonine,
can be used for treatment of resistance and/or intolerance to ≥2 TKIs.

47. ALLOGENIC STEM CELL TRANSPLATATION
• Allogeneic hematopoietic cell transplantation is a potentially curative
treatment option for medically-fit patients with advanced disease (
accelerated phase /blast phase ).
• HCT is occasionally offered for younger patients with chronic phase
(CP) CML who have a suitable donor and are not responding
adequately to TKI therapy.
• However, HCT is associated with significant early and late toxicity and
an increased rate of early mortality.
• A decision to proceed to allogeneic HCT must consider:
• Medically eligible
• Suitable donor

48. THANK YOU