Dr Nauman Butt – Royal Liverpool University Hospital CML Patient Seminar - 14 th November 2015...
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Transcript of Dr Nauman Butt – Royal Liverpool University Hospital CML Patient Seminar - 14 th November 2015...
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.
X
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