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 ( d.milojkovic@imperial.ac.uk )

Acknowledgements

• Tessa Holyoake, Glasgow

• Adam Meade, Oxford