CML & MPDs Practitioner Conference CML: Cases and interactive voting

1. CML & MPDs Practitioner Conference CML: Cases and interactive voting Brian Huntly University of Cambridge and Addenbrookes Hospital

3. 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

4. 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?

6. 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?

8. 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%

9. 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?

11. 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

12. 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)

13. 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

14. 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?

16. Case 2 • Patient reports that she is pregnant! • What would you do now?

18. 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?

19. 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

20. 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?

22. Case 2 • Patient continues on Dasatinib • Tissue typed and early discussions re transplant

23. Case 3 • Patient 3 28 y male diagnosis in 2005 • WCC 143, Spleen 12cm • Sokal/Hasford – Low • No siblings, caucasian background • Started IM 400mg

24. 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?

26. 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

27. Case 3 • 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?

29. 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

30. 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 )

31. Acknowledgements • Tessa Holyoake, Glasgow • Adam Meade, Oxford