Chronic myeloid leukemia

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

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.

3 phases of the disease

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%

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?

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

Questions in front

• Does upfront HSCT do any good?

• Does upfront 2G TKI are better than imatinib?

• Can we stop imatinib in CMR?

Upfront HSCT –evidence till date85- 95 % CHR

60-65%CCR

30-35%MMR

Imatinib

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

Bottom line

• No RCT in this

• Guidelines are still in imatinib as first line

• May come in future

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

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

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

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.

Diagnosis

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

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%

RQ PCR for BCR- ABL

• At diagnosis and 3 months- rate of fall in transcript

• 1 log reduction at 3 months predicts 70% vs13% chance of achieving MMR

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.

Monitoring during treatment

Monitoring during treatment

Definitions of response

Timeline to response

Treatment of chronic phase

Treatment of accelerated phase

Treatment of blast crisis phase

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.

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.

Toxicity of imatinib

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.

Management of other toxicity