Dr Nauman Butt – Royal Liverpool University Hospital

CML Patient Seminar - 14th November 2015

What is CML?How do we treat it?

Get up t o speed…

Chronic Myeloid Leukaemia (CML)• Basic biology• Clinical assessment – symptoms / diagnosis / staging /

prognosis• Treatment

– Short term considerations– Long term management

• Monitoring disease• Assessing response to treatment (milestones)• Role of stem cell transplantation

What is CML?

• CML is an overactive bone marrow disorder associated with an increase in white cells in the blood

• Characterised by the presence of the Philadelphia chromosome in the bone marrow

The Philadelphia chromosome

Regulating normal cell growth

Molecules bind to a cell receptors.These activate chemicals (or enzymes) called tyrosine

kinases (e.g. ABL) which control cell signalling.

Cell growth in CML

The Ph chromosome contains the BCR-ABL ‘fusion’ gene.The resulting BCR-ABL tyrosine kinase is permanently

switched ‘on’ - promoting uncontrolled cell growth.

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Symptoms• None or• Abdominal discomfort (caused by an enlarged spleen)• Fever, night sweats, weight loss• Aching joints and bones• Tired, weak • Breathless• Unusual bleeding / easy bruising• Infections• Visual disturbance

Diagnosis• FBC (WCC often in the >100x109/l)

– Blood film (and bone marrow)

• Cytogenetics (BM)– including tests for Philadelphia chromosome /

translocation (FISH)

• Molecular testing– measure BCR-ABL transcript levels by polymerase chain

reaction [PCR]

Staging – CML is a ‘triphasic’ disease

• Chronic phase (90%+ cases)– mainly excess of mature BM (myeloid) cells

• Accelerated phase– associated with more primitive cells (blasts) in BM

• Blast crisis– akin to acute leukaemia

Prognosis - predictors of treatment response / outcome

Scoring systems to utilise combinations of some or all of the following :

age, spleen size, individual cell counts• Sokal score (1984)

– Predictive of survival with ‘older’ therapies – low, intermediate, high risk

• Euro (or Hasford) score (1998)– Predictive of survival with ‘newer’ therapies – low, intermediate, high risk

• EUTOS score (2011) – Predictive of complete cytogenetic response and subsequent progression

free survival to ‘modern therapies’ – low, high risk

How do we treat CML?

– Short term considerations• Urgent / early interventions

– Long term management• Drug therapies

–availability of clinical trials• Role of stem cell (‘bone marrow’) transplant

How do we treat CML?• Short term considerations

- Immediate intervention to control white cell count- Physical / mechanical removal (leucoreduction)- Medication – hydroxycarbamide

- Stem cell collection (future potential transplant candidate)

- Fertility

How do we treat CML?

• Long term management

• Drug therapies

• availability of a clinical trial

• Stem cell (‘bone marrow’) transplant

Initial treatment(based on outcome of trials – including IRIS, SPIRIT 1 & 2 studies)

Traditional therapies

• Mostly historical (as initial therapy)

– Busulphan– Hydroxycarbamide*– Interferon*– Cytarabine

*have a current role in the management of some cases of CML

Modern ‘targeted’ therapies• Tyrosine kinase inhibitors

(TKIs)• Selectively ‘switch off’ BCR-

ABL tyrosine kinase

– Imatinib– Dasatinib– Nilotinib– Bosutinib– Ponatinib

Which TKI is best for me?

• Role of clinical trials • forthcoming SPIRIT 3 trial• commercial studies

• What’s new? (Prof Steve O’Brien) / Involvement in clinical trials (Prof Jane Apperley)

• Choice of first line therapy (Prof Mhairi Copland)

Measuring response to treatment

• Full blood count (FBC) – haematological response

• Bone marrow - cytogenetic response (measure Ph+ chromosomes in marrow)

• Molecular response - measure BCR-ABL transcript levels by PCR in blood

Goals of treatment

• Haematologic remission (normal blood cell count and physical examination (ie no spleen)

• Cytogenetic remission (normal chromosomes - 0% Philadelphia positive cells in marrow)

• Molecular remission (negative PCR for BCR/ABL)

Assessing response to treatment (milestones)

Measuring response to treatment

• Peripheral blood - molecular response (measure BCR-ABL – transcript levels by PCR)– Understand your PCR and ask some questions (Prof

Letizia Foroni)

Duration of therapy

• Traditionally treatment is indefinite / long term

• Unclear if this is necessary in the ‘best’ responders

• Trials evaluating dose reduction / stopping• Prospects for stopping? Should this be in a clinical

trial? (Prof Richard Clark)

When should we switch treatment?

– Intolerant to treatment• Side effects

–Common side effects and how can they be managed? (Dr Dragana Milojkovic ) ; Long term side effects: to include fertility & parenting (Dr Graeme Smith)

– Refractory (or unresponsive) to treatment• Failure to achieve recommended milestones

Alternative therapies

• Choice of second and third line therapies – Dependent on what agent was used first line

• Choosing second and third line drugs. How do we choose? (Dr Jenny Byrne)

Role of stem cell transplantation

• Those failing (or at highest risk of failing) standard TKI therapy (based on risk group / treatment response)

• Some patients presenting with or progressing to more advanced phase disease (accelerated / blast crisis)

• Transplant eligibility is dependent on patient fitness and donor availability

– What happens if you need a transplant? Dr Hugues de Lavallade

Summary• Basic biology• Clinical assessment – symptoms / diagnosis / staging /

prognosis• Treatment

– Short term considerations– Long term management

• Monitoring disease• Assessing response to treatment (milestones)• Role of stem cell transplantation