CML & MPDs Practitioner Conference CML: Cases and interactive voting
Brian HuntlyUniversity of Cambridge
and Addenbrookes Hospital
Case 1• 37 year old male
• WCC 80, Plts 840, Baso 6%, Blasts 2%, no spleen
• BCR-ABL positive, Sokal/Hasford low-risk
• 3 siblings
• Started on Nilotinib in ENEST trial, March 2011
Case 1• Patient entered CHR but problems with cytopenias
• Further cytopenias (Gd III thrombocytopenia and neutropenia) required dose interruption
• Early marrow 3 months of Nilotinib – Ph 40%, BCR-ABL:ABL ratio 43%
• Tissue typing demonstrates a fully matched sib
• What would you do now?
Case 1• Patient continued on Nilotinib
• 2 further 3 week interruptions due to cytopenias
• Repeat marrow at 6 months – 25% Ph positive, 31% BCR-ABL:ABL ratio 43%
• What would you do now?
Case 1• Patient continued on Nilotinib
• No further interruptions due to cytopenias
• Repeat marrow at 12 months – 0/200 cells Ph positive, BCR-ABL:ABL ratio 0.1%
Case 1• Patient continued on Nilotinib
• No further interruptions due to cytopenias
• Repeat marrow at 12 months – 0/200 cells Ph positive, BCR-ABL:ABL ratio 0.1%
• BUT – Karyotype shows 3 small separate clones - +6 8/200 +X 10/200
+ 8 20/200• NO evidence of dysplasia
• What would you do now?
Case 1• Patient continued on Nilotinib
• Repeat marrow at 18 months – ALL cells Ph-ve, ONLY + 8 18/200 cells
• Foe repeat marrow at 2 years and ?beyond
Significance of clonal abnormalities in Ph- clone following TKI?
• Incidence of clonal cytogenetic abnormalities in Ph NEGATIVE clone (CCA/Ph-) following TKI Rx varies (range of 2-17% of patients in described series)
• -7, -5, -Y and +8 most common
• Significance unknown
• Overall prognosis is good – one series of 515 patients – 30 CCA/Ph- patients with no difference in survival vs similar CCR patients (only 2/30 patients developed MDS median FU 51 months)
• MD Anderson- 1701 evaluable patients, 21 with CCA/Ph-, 3 developed other haem malignancies – (1 AML and 2 MDS-> AML)
Case 2• Patient 2 - 36 year old female lawyer
• Presented 2009 at 12 week booking – WCC 220, Plt 372, Spleen 3cm
• Sokal/Hasford – Low
• African ethnicity, 6 siblings
• Patient decided on a TOP
• Declined trial entry (SPIRIT 2, BELA) started Imatinib 400mg
Case 2• CHR at 3 months
• 6 month marrow – 18% Ph positive, BCR-ABL:ABL ratio 21%
• 1 year – 4% Ph pos, BCR-ABL:ABL ratio 9.7%
• What would you do now?
Case 2• Patient reports that she is pregnant!
• What would you do now?
Management of pregnancy in patients with CML
• Tyrosine kinase inhibitors are associated with adverse outcomes during pregnancy (180 pregnancies, 12 (7%) fetal abnormalities, 18 (10%) spontaneous abortions)
• Of the 63 normal births in the series 18 (29%) received IM for the duration of the pregnancy
• Risk of interrupting therapy to the patient - relates to degree of response seen before cessation (Kuwabara et al Blood 2010 – only 2/7 patients achieved ≥ MMR after reintroduction TKI, both had an optimal MMR response before stopping)
• Options for control of disease:
• α-IFN
• Leucapheresis
• Use of TKI in 3rd trimester?
Case 2• Imatinib stopped and patient discussed with fetal medicine – pregnancy
monitored as high-risk
• 18/40 loss of HR - α-IFN and dose titrated against SE, LMWH Rx instituted
• MTD 3MU/3 x per week
• 28/40, WCC 58 -Leucapheresis instituted weekly, total of 9 required
• Scans all normal with no evidence of IUGR
• Induced at 36 weeks in discussion with obstetricians
Case 2• Following delivery patient commenced upon Dasatinib, advised not to
breast feed, WCC 43, BCR-ABL: ABL ratio 117%
• CHR 3 weeks
• 3 months BCR-ABL: ABL ratio 64%• 6 months BCR-ABL: ABL ratio 9.9%• 12 months BCR-ABL: ABL ratio 1.3%, mutation screen negative• 18 months BCR-ABL: ABL ratio 0.9%
• What would you do now?
Case 2• Patient continues on Dasatinib
• Tissue typed and early discussions re transplant
Case 3• Patient 3 28 y male diagnosis in 2005
• WCC 143, Spleen 12cm
• Sokal/Hasford – Low
• No siblings, caucasian background
• Started IM 400mg
Case 3• CHR but not CCR(4% Ph+) after 1 year, BCR-ABL 2%
• IM increased to 600mg and then 800mg (2005-2007)
• Eventual CCR (~24/12), without MMolR, BCR-ABL: ABL ratio – 0.4-0.7%
• Mutation screen negative
• What would you do now?
Case 3• Patient changed to Dasatinib 100mg in May 2007
• No change in BCR-ABL: ABL ratio on 3/12 100mg
• Dasatinib increased to 140mg
• Slow but steady response over next next 2.5 years
• Achieved MMolR in Feb 2010 – continues on Dasatinib 140mg in MMolR
• Heart murmur picked up coincidentally 2012 – No symptoms
• Previous episode of palpitations 2008 – 24h Holter monitor and echo normal
• Repeat echo 2012– flow murmur, normal LV and RV function but increased pulmonary artery pressure suggested
• Confirmed by stressdoppler echo – Right heart catheterisation awaited
• ? Pulmonary Arterial Hypertension• ? Dasatinib related
• What would you do now?
Case 3
•Reduction in dasatinib (100mg, possibly 50mg) with CML response and PAH monitoring
•?Other TKI –which
•If PAH improves but molecular response worsens - ?Allo SCT
Case 3
Dasatinib and PAH – learning points
• Reports from 2009 onwards
• Incidence is not known – French registry 0.45% (Montani et al Circulation 2012)
• Majority of patients are symptomatic (exertional dyspnoea)
• Pre-capillary, mutation negative for inherited PAH, no other predisposition
• Withdrawl, dose reduction are recommended
• Reversible component upon cessation of Dasatinib – degree variable
• Consider if DAS patients with exertional dyspnoea, no evidence of pleural effusion, pulmonary oedema, anaemia or lung infiltration
• Registry for side-effects of TKI – Dragana Milojkovic Hammersmith ( [email protected] )
Acknowledgements
• Tessa Holyoake, Glasgow
• Adam Meade, Oxford
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