A brief discussion on Chronic Myeloid Lukaemia

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DR. MD. MAHAMUDUL HASAN

contents

• Epidemiology
• Cytogenetics
• Phases
• Risk stratification
• Treatment
• Follow up
• Management of TKI toxicities
• Management in special situations

Introduction

• CML is a myeloproliferative neoplasm characterized by rearrengemnent of long arm of chromosome 9 and 22 , resulting in the Philadelphia chromosome , creating the fusion oncogene BCR –ABL 1.
• Common in fifth and sixth decade, slight male predominance ,remains 1-2 : 100000 .
• Evidence from epidemiological study of Hiroshima and Nagasaki atomic bomb survivors ionizing radiation is a known risk factor.

Chronic Phase

• Around 95% are diagnosd in chronic phase with common presentation of unintentional weight loss , night sweat, fatigue and splenomegaly.
• Unlike other myeloproliferative disorder rarely associated with arterial or venous thrombosis.
• Dysplasia is uncommon , if present should prompt consideration of atypical CML.
• Increased reticulin fibers are seen in 30% cases and correlate with larger spleen size.

Accelerated phase

Definition by WHO

• PB or BM blast 10-19%
• PB basophils >20%
• Platelet <100000 /cc unrelated to therapy
• Platelet >1000000 /cc unresponsaive to therapy
• Clonal evolution on treatment
• Increasing spleen size and increasing WBC count unresponsive to therapy.

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Clonal evolution: Cytogenetic abnormalities additional to those found in baseline Ph+ clone are present at progression to AP.

Blastic Phasae

• 70 % of cases blasts are myeloid lineage and 25-30% express lymphoid antigens of B lineage.
• Altough mixed lineage leukaemia is rare , most cases bear t(9,22) lesion. These cases are recognized as a separate entity and made up of <1% of acute leukaemia.

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Cytogenetics

• The Ph+ chromosome was first linked to CML in 1960 by Nowell and Hungerford in Philadelphia .
• Rowley in 1973 showed that reciprocal translocation between the long arm of chromosome 9 and 22.
• The ABL 1 breakpoint is almost invariably located in the intron between exons 1 and 2, whereas BCR breakpoint usually occurs in an intron between exons 13-15.
• This resulting fusion transcripts are named e13a2 and e14a2 transcripts. These transcripts encode for a 210 kDa protein(M-bcr).

• e1a2 transcript encodes 190 Kda( m-bcr).
• e19a2 transcript encodes 230 kDa (micro-bcr).
• Also rare variants
• e6a2 transcripts encodes 195 kDa
• e8a2 transcript encodes 200 kDa
• e18a2 transcript encoides 225 kDa.

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• ABL1 is a tyrosine kinase ,but its activity was suppressed normaly. But juxtaposition of BCR and ABL1 promotes dimerization of BCR-ABL1 protein and ultimately tetramerization occurs which ultimately leads to autophosphporylation.
• Additionaly autoinhibitory myristate moiety of ABL 1 is lost by translocation events.
• These modifications leads activation of ABL1 which ultimately perform tyrosine kinase activity.

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• This tyrosine kinase activity results in cellular effects, such as

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• Loss of growth inhibition
• Decrease apoptosis
• Decrease adherence to the bone marrow stromal cells

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• Beside it many downstream pathway are also activated such as RAS/RAF/MEK/ERK/ERK, P13K/AKT, STAT , MYC.

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Risk calculation

• Sokal score
• Low <0.8
• Intermediate o.8-1.2
• High >1.2
• Hasford(EURO) score
• Low <780
• Intermediate >780- <1480
• High >1480
• EUTOS long term survival (ELTS) score.

Treatment of CML-CP

• Low- risk score:
• First generation TKI (IMATINIB 400 mg once daily)
• Second generation TKI (Dasatinib 100 mg once daily)
• Second generation TKI (Nilotinib 300 mg 12 hourly)
• Second generation TKI ( Bosutinib 400 mg once daily)
• Clinical trial
• Intermediate or High risk score
• Second generation TKI (Dasatinib 100 mg once daily)
• Second generation TKI (Nilotinib 300 mg once daily)
• Second generation TKI (Bosutinib 400 mg once daily)
• Imatinib 400 mg once daily
• Clinical trial

Treatment

• Accelerated Phase
• Second generation or third generation TKI (Bosutinib, Dasatinib,Nilotinib, Ponatinib)
• First generation TKI (Imatinib)
• Useful in certain circumstances : OMACETAXINE

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• Blast Phase

Lymphoid

• Clinical trial
• ALL type induction chemotherapy + TKI
• TKI + STEROID

Myeloid

• AML type induction chemotherapy +TKI
• TKI

Criteria for response and relapse

• Complete haematologic response:
• Complete normalization of peripheral blood counts with leucocyte count <10,000/cc
• Platelet count <450,000/cc
• No immature cells such as myelocytes, promyelocytes or blast in peripheral blood.
• No signs and symptoms of disease with resolution of palpable splenomegaly.

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• Cytogenetic response
• Complete cytogenetic response : No Ph- positive metaphases.
• Major cytogenetic responses : 0%- 35% Ph positive metaphases.
• Partial cytogenetic responses : 1%-35% Ph-positive metaphases.
• Minor cytogenetic responses : > 35%-65% Ph positive metaphases.

• Molecular responses :
• Early molecular responses : BCR- ABL 1 ≤10% at 3 and 6 months.
• Major molecular response BCR-ABL 1 ≤ 0.1% or ≥ 3 log reduction in BCR-ABL 1 transcripts from the standardized baseline, if qPCR is not available.
• Deep moleculer response BCR-ABL 1 ≤ 0.01%.

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• Relapse :
• Any sign of loss of haematological response.
• Any sign of loss of Complete Cytogenetic response or it’s molecular response correlate defined as an increase in BCR-ABL transcript to >1%.
• 1 log increase in BCR-ABL 1 transcript levels with loss of Major molecular response.

Treatment target recommended by ELN

Optimal warning failure

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3 month BCR-ABL ≤ 10 IS or BCR-ABL ≥10% IS No CHR or

≤35% Ph+ or 36-95% Ph+ ≥ 90% Ph+

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6 month BCR-ABL ≤1% IS or BCR-ABL 1-10% IS BCR-ABL >10% IS

0% Ph+ or 1-35% Ph + or Ph+ > 35%

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12 month BCR-ABL ≤ 0.1% IS BCR-ABL 0.1-1%IS BCR-ABL >1% IS or

> 0 % Ph+

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• According to ENL
• If failing IMATINIB switch to 2^nd generation TKI or PONATINIB and do HLA tissue typing.

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• If failing 2^nd generation TKI ,switch to an alternate 2^nd generation TKI or PONATINIB ,do HLA tissue typing and consider HSCT.

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• Consider results of mutation analysis and only use PONATINIB T315I cases.

• In general patient receiving TKI therapy should have BCR-ABL1 testing every 3 month for the first 2 years. Then every 3-6 months if MMR is achived.

Discontinuation of TKI therapy

• Age ≥ 18 years
• Chronic phase CML . No prior history of accelerated or blast phase.
• On approved TKI therapy for at least 3 years.
• Prior evidence of quantifiable BCR-ABL1 transcript.
• Stable molecular response ( MR4; BCR-ABL1 ≤0.01% IS) for ≥ 2 years, as documented on at least 4 tests, performed at least 3 months apart.
• Monthly molecular monitoring for the first 6 month , following discontinuation , 2 monthly during month 7-12, and 3 monthly thereafter (Indefinitely ) for patient who remain in MMR(MR3).

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Management of IMATINIB toxicity

• Dose : CML – CP recommended initial dose is 400 mg once daily

Accelerated phase or Blast phase dose is 600 mg once daily.

• Haematologic toxicities
• Chronic phase:

ANC <1000/cc and/or Platelet <50,000/cc - Hold imatinib until ANC >1500/cc and platelet >75,000/cc then restart at the starting dose (400 mg)

If recurrence occurs then after achieving target Imatinib should be restarted at reduced dose(300 mg).

• Accelerated phase and Blast Phase :

ANC <500/ cc and/or platelet <10,000/cc , cytopenia may or may not related to disease. If unrelated to disease reduce dose at 400 mg.

If cytopenia persists for 2 weeks reduce dose to 300 mg.

If persists for 4 weeks Imatinib should be stopped until ANC >1000/cc and platelet >20,000/cc and then restart treatment at 300 mg.

• Growth factor can be used if there is persistent neutropenia.
• If grade 3-4 anemia :
• Check reticulocyte count, ferritin, iron saturation, B12, folate.
• Nutritional deficiency should be corrected.
• Transfusion support , if symptomatic.

Management of DASATINIB toxicity

• Dose :CML- CP recommended dose 100 mg once daily

Accelerated phase or Blast phase 140 mg once daily

Haematologic toxicities:

Chronic phase :

• ANC <500/cc or Platelet <50,000/cc then hold dasatinib and restart at starting dose if recovery occurs within 7 days.
• If Platelet <25,000/cc or ANC <500/cc for >7 days then drug should be hold until ANC >1000/cc and platelet >50,000/cc ,then restart again at 80 mg for 2^nd episode and 50 mg for 3^rd episode.

• Accelerated Phase or blast phase :

ANC < 500/cc or platelet count <10,000/cc : Cytopenia may be related to disease . If unelated to disease , hold drug until ANC >1000/cc and platelet >20,000/cc then restart at starting dose.

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If recurrent episode happens then restart at 100mg for 2^nd and 80 mg for 3^rd .

Management of CML in Pregnancy

• TKI therapy with pregnancy there is higher risk of miscarriage and fetal abnormalities.
• A prolonged washout period needed prior to pregnancy while on TKI therapy.
• Fertility preservation should be discussed with all patient with childbearing age prior to starting TKI therapy.

• In case of male patient who on TKI therapy need not be discontinued if pregnancy is planned.
• The use of TKI therapy particularly during first trimester should be avoided. If TKI therapy is considered during pregnancy risk benefit ratio should be assessed.

• If treatment is needed it is preferable to initiate treatment with Interferons during pregnancy. Both Interferon alfa-2a and peginterferon alfa-2a is available.
• Hydroxyurea should be avoided in pregnancy ,specially in 1^st trimester.
• Leukapheresis can be used for a high WBC count.

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• Low dose aspirin or low molecular –weight heparin can be considered for patient with thrombocytosis.
• Monthly monitoring of qPCR is needed for those who receiving treatment other then TKI , and treatment should be started if increase >1%.
• TKI should be restarted after delivery. As TKI pass into human breast milk ,it should be advised not to breastfeed.